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Intramolecular alkylation of α,β-unsaturated ketones, an approach to the synthesis of zizaane type sesquiterpenoids… Zbozny, Michael 1978

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INTRAMOLECULAR ALKYLATION OF a,3-UNSATURATED KETONES, AN APPROACH TO THE SYNTHESIS OF ZIZAANE TYPE SESQUITERPENOIDS OF  AND THE TOTAL SYNTHESIS  (±) ISOLONGIFOLENE by MICHAEL ZBOZNY  B.Sc,  U n i v e r s i t y o f Guelph, 1969  M.Sc,  University  A THESIS SUBMITTED  o f Guelph, 1972  IN PARTIAL FULFILMENT OF  THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE STUDIES (Department of Chemistry)  We a c c e p t t h i s t h e s i s as conforming to the required standard  THE UNIVERSITY OF BRITISH COLUMBIA May, 19 7 8 (c) M i c h a e l Zbozny,  1978  In p r e s e n t i n g t h i s  thesis  an advanced degree at the L i b r a r y I  further  of  this  fulfilment of  the U n i v e r s i t y of B r i t i s h  s h a l l make it  freely  available  for  agree t h a t p e r m i s s i o n f o r e x t e n s i v e  for scholarly by h i s  in p a r t i a l  the  requirements  Columbia,  I agree  reference and copying o f  this  for  that  study. thesis  purposes may be granted by the Head of my Department or  representatives. thesis for  It  financial  i s understood that gain shall  written permission.  Department of The U n i v e r s i t y o f B r i t i s h 2075 Wesbrook P l a c e V a n c o u v e r , Canada V6T 1W5  Columbia  not  copying or  publication  be allowed without my  ABSTRACT  In  the f i r s t  alkylation  part  of t h i s  study i n v o l v i n g  thesis  an  intramolecular  4a-(3-chloropropy1)-4,4a,5,6,7,8—  hexahydro-2-(3H) - n a p t h a l e n o n e (77a) ,  4 a - ( 3 - i o d o p r o p y 1) - 4,4a,5,6,7,  8,-hexahydro-2(3H)-napthalenone(77b)  and  4a-(mesylate m e t h y l ) —  4,4a,5,6,7,8,hexahydro-2(3H)-napthalenone(95)  i s described.  Bicyclic  a, ^ - u n s a t u r a t e d k e t o n e s  and  prepared  and  under  their  a variety  cyclizations  of reaction  the case o f ketone  a c h i e v e d by v a r y i n g  reaction  parameters  a g e n t and The  leaving action  on o c t a l o n e and  ketone  system tion  certain  investigated. f o r a or  d'-alkyla-  base,  group.  a f f o r d e d ketone  (91) as t h e m i n o r  however, a f f o r d e d  lithium  of ketone  alcohol  (90) as t h e m a j o r p r o d u c t  product.  selectively  the ketone  (91) was  diisopropylamide  ketone  (92)  Bicyclic  A  change i n t h e  solvent  ketone  also  i n THF  (90).  alcohol  on  The octalone  (91) e x c l u s i v e l y .  Exclusive  a c h i e v e d by t h e a c t i o n  on k e t o n e  (77a).  addi-  A t no  of time  detected. ketone  angular p o s i t i o n The  The  complexing  of potassium t-butoxide i n t - b u t y l  (77a)  In  r e a c t i o n parameters.  of potassium t-butoxide i n t - b u t y l  formation  tions.  selectivity  alkylation  t o a 60/40 m i x t u r e o f THF/t-BuOH c o m b i n e d w i t h t h e  action  was  (95) were  v i a intramolecular  s t u d i e d were s o l v e n t ,  o f 18-crown-6 a f f o r d e d  (77b)  (77b)  c o n d i t i o n s was  (77a) h i g h  t i o n was  (77a),  was  position  (95) h a v i n g a m e s y l a t e m e t h y l g r o u p subjected  t o a number o f r e a c t i o n  o f a l k y l a t i o n was  f o u n d t o be  a t the  condi-  dependent  iii  on s o l v e n t and the presence of 18-crown-6. l i t h i u m t - b u t o x i d e or potassium or  THF  on ketone  ketone  The  a c t i o n of  t-butoxide i n t - b u t y l  (95) a f f o r d e d e x c l u s i v e l y ketone  (66).  (104) as the major product and ketone  the minor p r o d u c t . In  Ketone  (103) was  (114)  from  hexahydro-2-(3H) -napthalenone methyl  i o d i d e of  Octalone  as  not d e t e c t e d .  4a-(carbomethoxy)-4a,4,5,6,7,8— (97) i s d e s c r i b e d .  A l k y l a t i o n with  (97) a f f o r d e d the d i m e t h y l a t e d o c t a l o n e  (146) was  transformed i n t o o c t a l o n e  hydroborated  u s i n g d i s i a m y l b o r a n e i n THF  mixture of a l c o h o l s (148) and  (149) was  Diene and the  bromosuccinimide  allylically  i n dioxane  keto a c e t a t e s (155)  and  resultant acetic  (154).  o x i d i z e d by the a c t i o n o f  The  N—  i n the presence o f l i g h t t o y i e l d  (156).  Decarbomethoxylation  keto a c e t a t e s f o l l o w e d by k e t a l i z a t i o n of r e s u l t a n t a f f o r d e d k e t a l a c e t a t e (160). (160)  (147)  acetylated with  anhydride and p y r i d i n e to a f f o r d a c e t a t e s (153) and l a t t e r mixture was  (146).  (147) v i a a W i t t i g  r e a c t i o n u s i n g methylenetriphenylphosphorane.  t i o n of  (66)  the second p a r t of t h i s t h e s i s a 15-step s y n t h e s i s of  (±) i s o l o n g i f o l e n e  (161)  The  (95) i n HMPA, with or without 18-crown-6, however  a f f o r d e d ketone  was  alcohol  of the mixture  L i t h i u m aluminum h y d r i d e reduc-  f o l l o w e d by t o s y l a t i o n of the r e s u l t a n t  afforded ketal tosylate  alcohol  (162). A c i d h y d r o l y s i s of  (162)  f o l l o w e d by i n t r a m o l e c u l a r a l k y l a t i o n of the r e s u l t a n t keto tosylate  (163)  a f f o r d e d the t r i c y c l i c o c t a l o n e  genation of the l a t t e r u s i n g DDQ  (165).  y i e l d e d dienone  Dehydro-  (166) which  when t r e a t e d w i t h l i t h i u m d i m e t h y l c u p r a t e i n e t h e r a f f o r d e d octalone  (167).  Treatment  of  (167) w i t h p y r i d i n i u m hydrobromide  iv  perbromide f o l l o w e d by dehydrobromination of the r e s u l t a n t crude bromide The  (168)  l a t t e r was  a f f o r d e d the c r o s s conjugated  converted  i n t o octalone  (124)  (124)  not converted  into  ketone  (169).  v i a a methyl  cuprate  reaction. Octalone  was  s i n c e t h i s t r a n s f o r m a t i o n had Dienone nitrile  (172)  the former.  (166)  was  (±) i s o l o n g i f o l e n e  a l r e a d y been r e p o r t e d .  converted  into  a, B-unsaturated  by the a c t i o n of d i e t h y l aluminum cyanide T h i s t r a n s f o r m a t i o n was  keto on  to e v e n t u a l l y p r o v i d e  e n t r y i n t o the zizaane c l a s s of s e s q u i t e r p e n o i d s .  an  V.  TABLE OF CONTENTS Page PART I INTRODUCTION I.  II.  INTERMOLECULAR ALKYLATION OF a, 3-UNSATURATED KETONES . . . (A) GENERAL COMMENTS . . . (B) ALKYLATION OF ENOLATE ANIONS FORMED UNDER KINETICALLY CONTROLLED DEPROTONATION . . . (C) ALKYLATION OF ENOLATE ANIONS FORMED UNDER THERMODYNAMICALLY CONTROLLED DEPROTONATION (D) METHODS FOR THE OVERALL MONOALKYLATION OF a, 3-UNSATURATED KETONES AT THE POSITION . . .  13  INTRAMOLECULAR ALKYLATION OF KETONES . . .  20  (A)  20  (B) III.  SATURATED KETONES . . . a,3-UNSATURATED KETONES AND ALDEHYDES . . .  THE PROBLEM . . .  1 1 6 9  24 30  DISCUSSION I. PREPARATION OF 4a-(3-CHLOROPROPYL)-4,4a,5,6,7,8 — HEXAHYDRO-2-{3H) - N A P T H A L E N O N E (77a) and 4a- (3—r IODOPROPYL) -4, 4a,5, 6, 7, 8-HEXAHYDRO-2-(3H) — NAPTHALENONE(77b) . . .  31  II.  INTRAMOLECULAR ALKYLATION STUDY . . .  41  (A) (B)  GENERAL CONSIDERATIONS . . . INTRAMOLECULAR ALKYLATION INVOLVING 4a— (3-CHLOROPROPYL)-4a,4,5,6,7,8-HEXAHYDRO— 2-(3H)-NAPTHALENONE (7 7a) . . .  41  1. 2. 3. 4. 5.  44 46 47 49 49  (C) (D) (E)  General . . . Effect of Solvent . . . Effect of Base . . . Effect of Complexing Agent . . . Synthetic Application . . .  INTRAMOLECULAR ALKYLATION INVOLVING 4a— (3-IODOPROPYL)- 4a,4,5,6,7,8-HEXAHYDRO— 2-{3H)-NAPTHALENONE (77b) . . . SUMMARY OF INTRAMOLECULAR ALKYLATION STUDY STRUCTURAL ASSIGNMENT OF ALKYLATION PRODUCTS . . .  44  51 54 55  vi Page  III.  PREPARATION OF 4a-(MESYLATE METHYL)-4a,4,5,6,7,8— HEXAHYDRO- 2-{ 3H) -NAPTHALENONE (95) . . .  58  IV.  INTRAMOLECULAR ALKYLATION STUDY INVOLVING 4 a — (MESYLATE METHYL)-4a,4,5,6,7,8-HEXAHYDRO-2(3H) — NAPTHALENONE (95) . . .  64  (A) (B)  GENERAL COMMENTS . . . INTRAMOLECULAR ALKYLATION OF MESYLATE 1. General 2.. E f f e c t of S o l v e n t . . . 3. E f f e c t o f Base . . . 4. E f f e c t o f Complexing Agent . . . 5. S y n t h e t i c A p p l i c a t i o n . . .  (C)  STRUCTURAL ASSIGNMENT OF ALKYLATION PRODUCT  (95)  EXPERIMENTAL  64 67 67 69 74 77 78 79 82  PART I I SYNTHETIC STUDIES ON ZIZAANE-TYPE SESQUITERPENOIDS AND THE TOTAL SYNTHESIS OF (±)-ISOLONGIFOLENE INTRODUCTION  105 .  I.  GENERAL REMARKS . . .  105  II.  STRUCTURE AND PREVIOUS SYNTHESIS OF ( ± ) — ISOLONGIFOLENE . . .  108  III.  STRUCTURE AND PREVIOUS SYNTHESIS OF SOME ZIZAANE— TYPE OF SESQUITERPENOIDS . . . I l l  DISCUSSION  126  I.  GENERAL APPROACH . . .  126  II.  TOTAL SYNTHESIS OF  133  III.  AN APPROACH TO THE ZIZAANE CLASS OF SESQUITERPENES  (±) ISOLONGIFOLENE . . .  153  EXPERIMENTAL  156  REFERENCES  174  L I S T OF TABLES Page Table  I  52  Table  II  75  viii  ACKNOWLEDGEMENT  I t i s a w e l l known f a c t t h a t t h e w r i t i n g o f a t h e s i s r e q u i r e s t h e h e l p o f many p e o p l e and I w o u l d l i k e t o take t h i s o p p o r t u n i t y t o thank the f o l l o w i n g persons f o r t h e i r contributions. I a c k n o w l e d g e t h e g u i d a n c e and e n c o u r a g e m e n t o f Dr. Edward P i e r s . This i s procedure. I am a l s o o b l i g e d t o p r a i s e t h e p a t i e n c e he has e n d u r e d and t h e u n d e r s t a n d i n g t h a t he has shown. This recognition i s t r a d i t i o n a l . I must a l s o t h a n k him f o r s o m e t h i n g more: n a m e l y ' h i s p e r s o n a l i t y and t h e t i m e he t o o k t o s h a r e i t w i t h me. I e n j o y e d i t . E d , y o u make i t look easy. I am a l s o i n d e b t e d t o t h e o t h e r members; b o t h p a s t and p r e s e n t , o f o u r r e s e a r c h g r o u p as w e l l as members o f Dr. K u t n e y ' s g r o u p f o r t h e many w o r t h w h i l e d i s c u s s i o n s . Specia t h a n k s a r e due t o D. H e r b e r t and Dr. P.M. Worster. Paul, for h i s a d v i c e and i n v a l u a b l e e n t h u s i a s m i n t h e e a r l y s t a g e s o f my research. And, Dave, f o r b e i n g c o n s i s t e n t w i t h h i s k n o w l e d g e and c o n c e r n t h r o u g h o u t and f o r h i s p r o o f r e a d i n g .  Dave, who  The M a c m i l l a n b r o t h e r s w i l l n o t be s e t t h e c h a l l e n g e , and Chub who w i l l  forgotten. a l w a y s be t h e r e .  ix  To Malcolm and D a v i d  MacMlllan  -1-  INTRODUCTION I.  ALKYLATION OF • a 3-UNSATURATED  INTERMOLECULAR (A)  GENERAL Since  primarily with a 3 -unsaturated the  alkylation  COMMENTS  the f o l l o w i n g p o r t i o n o f t h i s the intramolecular a l k y l a t i o n ketones,  o f a B-unsaturated ketones.  o f a resonance s t a b i l i z e d  accomplished  Generally, the  dienolate anion.  solvent. a  forms t h e l e s s  kinetically  This i s  s t a b l e d i e n o l a t e anion  c o n t r o l l e d a b s t r a c t i o n o f an  with  I t h a s b e e n shown^"  t h e a c t i o n o f s t r o n g b a s e on an ,$ - u n s a t u r a t e d  initially  is  o f a number o f  the a 3-unsaturated ketone  by t r e a t i n g  a s t r o n g b a s e i n an a p p r o p r i a t e that  deals  ketone r e q u i r e s the i n i t i a l  (  usually  thesis  i t i s pertinent to discuss i n general  a l k y l a t i o n o f an a 8 - u n s a t u r a t e d formation  KETONES  ketone  ( A ) , by t h e  of p r o t o n .  The  process  shown i n e q u a t i o n ( I ) .  The reaction  f a t e of the d i e n o l a t e anion c o n d i t i o n s a n d on t h e - n a t u r e  ated ketone alkylating  (1). agent,  Dienolate  anion  (A) w i l l  d e p e n d on t h e  of the parent  a,3-unsatur-  (A) c a n e i t h e r r e a c t w i t h t h e  t o form a l k y l a t e d p r o d u c t ,  o r can, i n the  -2-  presence and  of a suitable proton  be c o n v e r t e d b a c k t o t h e o r i g i n a l  (see  transfer  a,£-unsaturated  ketone  equation ( 2 ) ) .  (1)  If  lated  (A)  the r e a c t i o n  faster  in  s o u r c e , undergo p r o t o n  than proton  (2)  conditions transfer,  are such (rate  p r o d u c t w o u l d be f o r m e d .  ketone  dienolate  (1) w i l l anion  a position,  form  (B).  initially  that  alkylation i s  k a r a t e K_^) , t h e n t h e a l k y -  Abstraction  o f t h e gamma p r o t o n  the thermodynamically  The l a t t e r forming  i s usually  more  stable  alkylated  a t the  the 6 - a l k y l a t e d - £ y-unsaturated y  2 ketone  (3)  .  The o v e r a l l p r o c e s s  R  (1)  3.  i s shown i n e q u a t i o n  (3)  1  .(3),  -3-  Ketone ketone tion,  (3) may  i s o m e r i z e t o an « - a l k y l - a , ^ - u n s a t u r a t e d  (7), v i a d i e n o l a t e a n i o n also v i a d i e n o l a t e anion  g,y^unsaturated  ketone  (6) .  (5), t o f o r m  the l a t t e r  product  the a / a - d i a l k y l a t e d - g y -unsaturated  is  of  either  below.  as t h e m a j o r  ketone  (6).  The  l e a d i n g t o t h e f o r m a t i o n o f d i e n o l a t e a n i o n (5),  t h e p r e d o m i n a n t pathway b e c a u s e  saturated- ketone  alkyla-  cc, a - d i a l k y l a t e d —  predominates g i v i n g ;  process,  further  These r e a c t i o n s a r e o u t l i n e d  Usually  latter  process  (5), o r u n d e r g o  the a proton  (3) i s k i n e t i e a l l y  more a c i d i c  the s t a r t i n g a,g-unsaturated  (6)  ketone  (5)  a - a l k y l - a,3-unsaturated  ketone  (7).  o f t h e 3 ,^-unthey  than  protons  (1) o r t h e  ' The i n t e r m e d i a t e  (7) (5) 2  then The  undergoes i r r e v e r s i b l e o v e r a l l process  alkylation  t o form  i s d e p i c t e d i n Scheme I .  compound  (6) .  -4-  R* R* (6).  R,R'=alkyl X =halide  R' (5)  SCHEME I  R.' (7)  -5-  From Scheme I i t i s c l e a r t h a t treatment o f an a , g-unsaturated ketone w i t h base and an a l k y l a t i n g reagent can l e a d t o a complex mixture of p r o d u c t s , i n c l u d i n g compounds o f the type (2),  ( 3 ) , (6) and (7).  R'R'  (6)  R'  (7)  C l e a r l y , i t would be advantageous, from a s y n t h e t i c p o i n t of view, t o be a b l e t o c o n t r o l the type o f product formed.  In  summary, t h e problems a s s o c i a t e d w i t h the a l k y l a t i o n o f a ^ - u n s a t u r a t e d ketone  systems are t h r e e f o l d .  F i r s t l y , how does one  s e l e c t i v e l y form one o f the two p o s s i b l e d i e n o l a t e anions (B)?  Secondly, how does one s e l e c t i v e l y a l k y l a t e one o f the  two p o s s i b l e d i e n o l a t e anions one  (A) o r  (A) o r (B)? L a s t l y , how does  stop the a l k y l a t i o n , o f e i t h e r d i e n o l a t e anion  l a t e anion  (B), a t the m o n o a l k y l a t i o n  stage?  (A) o r dieno-  -6-  (B)  ALKYLATION OF  ENOLATE ANIONS FORMED UNDER KINETICALLY  CONTROLLED DEPROTONATION The cussed  first  two  p r o b l e m s m e n t i o n e d above c a n be  t o g e t h e r s i n c e they  kylation  of a s p e c i f i c  vided  a n i o n has  of course  time.  The  sidering  rate  first  (4) .  This  o f one  has  bases.  I t has  ketone ct p r o t o n  the r e a c t i o n the  That one  the  the  i s to say,  may  then  initial  once a  alkylate  w i t h s t r o n g base w i l l t o form  lifeby  effect  dienolate anion  (A).  that r a t e ^ r a t e _ ^  f o r m a t i o n of the d i e n o l a t e anion  by  i t , pro-  a sufficient  been a p p r o a c h e d  specific  con-  b e e n shown^" t h a t t r e a t m e n t  c o n d i t i o n s such  been a c c o m p l i s h e d To p r o l o n g  i n t h a t the a l -  f o l l o w s from  o f t h e s e p r o b l e m s has  would ensure  0  related  t h a t t h e e n o l a t e a n i o n has  an-a^,3"unsaturated  trolling  enolate.  been g e n e r a t e d ,  equation  straction  closely  enolate anion  g e n e r a t i o n of a s p e c i f i c enolate  are  dis-  employing  lifetime  lithium  of  the  ab-  Conor (A).  d i a l k y l a m i d e s as  of d i e n o l a t e anion  (A) t h e  reac-  -7-  t i o n i s u s u a l l y c a r r i e d out i n an a p r o t i c s o l v e n t and a t low temperatures.  By u s i n g a r e a c t i v e a l k y l a t i n g agent  selective  a l k y l a t i o n o f the k i n e t i c a l l y p r e f e r r e d e n o l a t e can be achieved ( r a t e ^ r a t e ^) .  Below are a few examples o f a' a l k y l a t i o n o f  a ^ - u n s a t u r a t e d ketone  systems.  (8)  (9)  Thus W. Reusch e t a l '  (10)  found t h a t treatment o f pulegone  (8)  w i t h l i t h i u m i s o p r o p y l c y c l o h e x y l a m i d e i n THF* a t 0° f o l l o w e d by the a d d i t i o n o f methyl i o d i d e a f f o r d e d the (9) as the major p r o d u c t i n 56% y i e l d . ketone  (10), was the product o f  a-alkylated  ketone  The minor product,  ff-alkylation.  Similarily  they  found, t h a t under the same c o n d i t i o n s , cholest-4-ene-3-one and 5,5-dimethylcyclohex-2-ene-l-one rivatives  (12), gave  d i m e t h y l de-  (13) and (14), r e s p e c t i v e l y , as the predominant  Bucourt e t a l ^ have shown t h a t  (11)  products.  c/'alky l a t i o n can be achieved  by u s i n g potassium t - b u t o x i d e as base and by working a t low  * T e t r a h y d r o f u r a n - THF  -8-  (12)  (14)  temperatures THF  (-70  s o l u t i o n of  ether  ) i n an a p r o t i c s o l v e n t .  of a  17-methyl-19-nortestosterone-tetrahydropyranyl  (15) and methyl i o d i d e  potassium  Thus, treatment  t - b u t o x i d e i n THF  (1 e q u i v a l e n t ) a t -70°, w i t h f o r 1.5  hours, r e s u l t e d i n the  mation of the monomethylated n o r t e s t o s t e r o n e (16).  (15) more methyl i o d i d e d i m e t h y l a t e d p r o d u c t  By  excess for-  employing  (16) (17) was  formed as  the  -9-  major  product.  OTHP  (17)  Thus, i t has been p o s s i b l e the k i n e t i c a l l y by m o d i f y i n g tion  preferred  the r e l a t i v e  of the i n i t i a l l y (C)  lithium  and m o n o a l k y l a t e  and p o t a s s i u m  rates of alkylation  enolate  anions  and i s o m e r i z a -  formed d i e n o l a t e a n i o n .  ALKYLATION OF ENOLATE ANIONS FORMED UNDER  THERMODYNAMICALLY Formation  CONTROLLED DEPROTONATION  o f the d i e n o l a t e anion  n a m i c a l l y more s t a b l e under e q u i l i b r a t i n g t-butoxide these  t o generate  than d i e n o l a t e anion  c o n d i t i o n s u s i n g bases  i n a protic  s o l v e n t such  c o n d i t i o n s 'dienolate anion  of dienolate anion  ( B ) , (thermody(A)), i s accomplished such  as t - b u t y l  as p o t a s s i u m alcohol.  Under  (B) i s f o r m e d a t t h e e x p e n s e  (A): i . e . , the equilibrium  i s allowed t o  2 be  established  i n favour of the d i e n o l a t e anion  cally,  treatment  result  i n alkylation  atom.  In p r a c t i c e ,  (B).  o f t h e l a t t e r w i t h an a l k y l a t i n g at either  Theoreti-  agent  t h e a l p h a o r t h e gamma  could  carbon  C - a l k y l a t i o n o c c u r s p r e d o m i n a n t l y at the^  -10-  .(A)  (1)  (B)  a.. c a r b o n J the carbon b e a r i n g the h i g h e s t t o form a  ^y-unsaturated  ketone  (3).  electron density The i n i t i a l  may be i s o m e r i z e d to an d - a l k y l - a . , 6 -unsaturated  product  ketone  may undergo f u r t h e r a l k y l a t i o n to form the d i a l k y l a t e d ketone  (6).  R'R  1  (6)  R  1  (5)  R  '  1  (7)  (7)  , (3) or  product  -11-  D i a l k y l a t i o n has o f t e n been the major process because the a -proton o f ketone gamma protons o f ketone  (3) i s more r e a d i l y a b s t r a c t e d than the (7) o r the gamma protons o f the i n i t i a l 2 6  starting  - u n s a t u r a t e d ketone  (1) ' .  Below are a few  examples o f the a l k y l a t i o n o f the thermodynamically  favoured  e n o l a t e anions d e r i v e d from a number o f a^B - u n s a t u r a t e d  ketones  p o s s e s s i n g a gamma p r o t o n .  (19) Thus, when excess methyl  (21) i o d i d e i s added, a t room temper-  a t u r e , t o a s o l u t i o n o f e i t h e r compound  (18) o r (19), which  has been p r e v i o u s l y t r e a t e d w i t h potassium t - b u t y l a l c o h o l , the 4,4-dimethyl/f-3-one  t-butoxide, i n compounds  (20)  and  9 10 (21) were i s o l a t e d i n good y i e l d r e s p e c t i v e l y ' Alpha a l k y l a t i o n i s the r u l e and gamma a l k y l a t i o n i s r a r e .  -12-  Below a r e two examples where gamma a l k y l a t i o n has been observed as the minor p r o d u c t . 0  0  0  75-80%  10-15%  One example where gamma a l k y l a t i o n has been observed as the major p r o d u c t i s shown below. synthesis of a pentacyclic  Snieckus e t a l " ^ i n t h e i r  a l k a l o i d model system employed  as t h e i r key step the gamma a l k y l a t i o n o f an a; 3-unsaturated , amide.  Thus treatment o f the a, 3-unsaturated amide  (22) w i t h  2 e q u i v a l e n t s o f n - b u t y l l i t h i u m i n TMEDA* and e t h y l bromide afforded  the gamma a l k y l a t e d  a, 3 -unsaturated amide (23).  *TMEDA - Tetramethylenediamine  -13-  (D)  METHODS FOR THE OVERALL MONOALKYLATION OF  a,e-UNSATURATED KETONES AT THE  a POSITION  Thus f a r I have d i s c u s s e d t h e a l k y l a t i o n anions tions  formed under k i n e t i c a l l y as w e l l as t h e a l k y l a t i o n  thermodynamically third  problem  ated ketones  controlled  concerns  controlled  of enolate  deprotonation condi-  o f enolate anions  formed  deprotonation conditions.  under The  t h e o v e r a l l m o n o a l k y l a t i o n o f ot, 8 - u n s a t u r -  a t the a-position.  Pictorally,  the o v e r a l l  t r a n s f o r m a t i o n r e q u i r e d i s shown i n e q u a t i o n ( 5 ) .  Stork amines.  has s o l v e d t h i s The o v e r a l l p r o c e s s  problem  by m a k i n g u s e o f m e t a l l o e n e -  i s shown b e l o w .  The  a.B-unsatur-  -14ated ketone to be monoalkylated is first transformed into an N-alkylimine derivative.  More specifically, treatment of 10—  methyl- A ' -2-octalone (24) with excess cyclohexylamine in re1  9  fluxing toluene containing a catalytic amount of p-toluenesulfonic acid afforded, in quantitative yield, the N-cyclohexylimine (25). A THF solution of imine (25) was allowed to react, under an atmosphere of nitrogen, with slightly less than one equivalent  (28) of lithium diisopropylamide.  (29) After refluxing for 8 hours an ex-  cess of methyl iodide in THF was added and reflux was continued an additional overnight period.  The resulting crude monoalky-  lated imine was hydrolyzed with hot  aqueous sodium acetate-  acetic acid-water (1:2:2) for four hours.  Isolation afforded a  95% recovery consisting of about 90% monoalkylated a £-unsatur;  ated ketone (28) and 10% of the starting unalkylated ctj g-unsaturated ketone (24) .  -15-  Similarily,  isophorone-N,N-dimethy1 hydrazone  (29) when  t r e a t e d w i t h one e q u i v a l e n t of sodium h y d r i d e i n THF  10% hexamethylphosphoramide 1-iodobutane 6N HCl The  containing  (HMPA) f o l l o w e d by r e a c t i o n w i t h  (3 h r s , room temperature)  (1 hr) gave n - b u t y l i s o p h o r o n e  and h y d r o l y s i s w i t h hot (30) i n 70%  yield.  r e a c t i o n o f a l k y l G r i g n a r d reagents w i t h N,N-dimethyl-  hydrazones of a,3-epoxyketones has a l s o been f r u i t f u l i n accomplishing  overall  alpha m o n o a l k y l a t i o n of a, g - u n s a t u r a t e d 15  The  secruence i s shown i n 31—>32.  0 (31)  I  /  N  N  \  *  H  OH  ketones,  -16-  To i l l u s t r a t e the f e a s i b i l i t y o f the above sequence a d e t a i l e d account u s i n g isophorone as s u b s t r a t e f o l l o w s .  (34)  Thus, isophorone oxide  ( 3 3 ) , made by standard methods from  isophorone, was allowed t o r e a c t w i t h 2 eq. o f N,N-dimethylhydrazine and 0.5 eq 0°.  of proprionic  acid i n ethyl acetate at  A f t e r f o r t y minutes t h e r e a c t i o n mixture was t r e a t e d  with  10% aqueous sodium carbonate and the N,N-dimethylhydrazone ( 3 4 ) , as a 1:1 mixture o f syn and a n t i isomers, was i s o l a t e d i n 95% yield.  When the l a t t e r mixture was t r e a t e d w i t h 1.5 e q u i v a -  l e n t s of phenylmagnesium bromide  (THF, ^  room  temperature,  1.5 h o u r s ) , and the r e s u l t a n t crude product was h y d r o l y z e d with 3N HCl i n 50% aqueous e t h y l a l c o h o l phorone  f o r 1 hour,  2-phenyl  iso-  (35) was o b t a i n e d i n 77% y i e l d .  S y n t h e s i s o f (35), (R=methyl, b u t y l , and 3-methoxyphenethyl) was  accomplished  i n y i e l d s o f 63, 65 and 61% r e s p e c t i v e l y by  u s i n g the proper G r i g n a r d reagent.  -17-  R=Phenyl, M e t h y l ,  Butyl,  3-Methoxy P h e n e t h y l  (35)  Another approach to the problem of monoalkylation o f ct^p - u n s a t u r a t e d k e t o n e s w o r t h y Corey  et a l ^ .  The m e t h o d o l o g y  o f m e n t i o n has b e e n involved  i s shown  OH  d e v e l o p e d by below.  (CH ) Cu 3  / N  I  "0  H0>  0-  C  H  ^ 2  C  U  11  0  -0  OH  2  -18-  To i l l u s t r a t e the f e a s i b i l i t y of the above proposed  scheme  16 Corey e t a l  converted 2,3-epoxycyclohexanone i n t o t r a n s - 3 —  hydroxy-2-methylcyclohexanone i n the f o l l o w i n g manner.  Oxime  was  of the  o b t a i n e d from the corresponding ketone by treatment  l a t t e r with 1.1 2.2  e q u i v a l e n t s of hydroxylamine  h y d r o c h l o r i d e and  e q u i v a l e n t s of sodium a c e t a t e i n methanol a t 0 ° c  minutes.  The  oxime  (36) i n e t h e r was  e q u i v a l e n t s of l i t h i u m dimethylcuprate the r e a c t i o n was i n ether.  (37). i n THF was  f o r 30  then added to f i v e at 25°C (1.25 hours)  quenched below - 2 5 ° c with c o l d 10%  Crude. oxime N-OH  (36)  acetic  and acid  t r e a t N-OH ed with 2 equivalents  (38a)  (38)  of aqueous t i t a n i u m t r i c h l o r i d e and 12 e q u i v a l e n t s of ammonium a c e t a t e at 0 ° c  f o r one hour. E v a p o r a t i o n of the s o l v e n t  gave trans-3-hydroxy-2-methylcyclohexanone a c o l o u r l e s s o i l of 90-95% p u r i t y . compound  (38)  (and s i m i l a r  (38a^.  as  I t should be noted t h a t  6-hydroxy ketones) i s i n general,  r a t h e r unstable and e a s i l y dehydrated ketone  (38) i n 90% y i e l d  ;  to the a, B - u n s a t u r a t e d  Thus, o v e r a l l m o n o a l k y l a t i o n of an .a B — u n s a t u r -  ated ketone has been achieved.  -19-  One ketone,  f i n a l example of m o n o a l k y l a t i o n of an a 3 -unsaturated i n v o l v e s the monomethylation of the morpholine  enamine  19 17 d e r i v e d from A '• - o c t a l o n e - 2 .  Thus, treatment  of  (39) w i t h one e q u i v a l e n t of methyl i o d i d e  f o r twenty hours i n r e f l u x i n g dioxane l a t e d enamine  (40).  H y d r o l y s i s o f - t h e l a t t e r w i t h sodium  a c e t a t e - a c e t i c acid-water o f ketones  gave the crude monoalky-  (41) and  (42).  ( r e f l u x 4 hours) y i e l d e d a mixture The  g y -unsaturated ketone  converted i n t o the a 3 -unsaturated ketone ;  the former with 4% methanolic potassium  (41)  (42) by treatment  hydroxide.  was of  -20-  I I . INTRAMOLECULAR (A)  ALKYLATION OF KETONES  SATURATED KETONES Since t h i s t h e s i s i s mainly concerned with  molecular  a l k y l a t i o n o f a 3 - u n s a t u r a t e d ketones i t i s deemed /  appropriate molecular  the i n t r a -  a t t h i s time to d i s c u s s , i n g e n e r a l , the i n t r a -  a l k y l a t i o n of a 3 -unsaturated ?  ketones as w e l l as the  i n t r a m o l e c u l a r a l k y l a t i o n o f s a t u r a t e d ketones.  The g e n e r a l  theory  i s as f o l l o w s . I f the a n i o n i c carbon atom  (marked  the l e a v i n g group t o be d i s p l a c e d by two o r more carbons, the product tion 6).  (*)) o f an e n o l a t e and  (marked  (x)) are separated  w i l l be c y c l i c  (see equa-  The value o f n determines the r i n g s i z e and, i n  g e n e r a l , the r e l a t i v e r a t e s o f r i n g c l o s u r e , to form v a r i o u s  r i n g s i z e s , i s 3^> 5^>6)7^4, 8/> l a r g e r r i n g s o r i n t e r m o l e c u l a r 2 reactions  .  Because o f the very high r a t e o f formation  o f three  membered r i n g s , c y c l o p r o p y l compounds can be s u c c e s s f u l l y s y n t h e s i s e d u s i n g very m i l d r e a c t i o n c o n d i t i o n s . However, 18 ease of r i n g formation i s not synonymous w i t h r i n g s t a b i l i t y  -21-  Although pected  the energy required  to reflect  f o rring  the s t a b i l i t y  must be c o n s i d e r e d .  closure  o f the product other  One i m p o r t a n t  of the reacting  other.  increases  tion for in the  decreases.  Overall,  t h r e e membered r i n g s  initial  tially  s i t e s approaching  the p r o b a b i l i t y  ease o f f o r m a t i o n because the three  t h e optimum p o s i t i o n  for ring  ROOC v  to give  closure.  However, o n c e with  2  formed,  the i n i -  a c y c l i c compounds a s shown b e l o w .  19  COOR  Base  CH  of cycliza-  atoms a r e n e c e s s a r i l y  CH„—Br  WOC '  each  i s r e l a t i v e l y high  p r o d u c t s may be c a p a b l e o f r e a c t i n g  formed a n i o n  factors  f a c t o r w h i c h must be c o n s i -  dered i s the p r o b a b i l i t y As t h e r i n g s i z e  m i g h t be e x -  Br  'COOR COOR CH 00R  COOR  COOR H -C-COOR f  (CH' ) ~ I H - C-COOR  COOR  l  COOR  Intramolecular alkylations synthesis  of a variety  have f o u n d  application  o f p o l y c y c l i c compounds.  p r o v i d e s many e x a m p l e s where i n t r a m o l e c u l a r been t h e c r u c i a l s t e p formation o f carbon (+)-copacamphor  i n the synthetic  (44).  The l i t e r a t u r e  alkylations  design  f r a m e w o r k s as v a r i e d  for the  leading  as a t i s i n e  have  to the (43)  and  -22-  .o  \  ' N  H  (44)  (43) Although i t i s not p o s s i b l e t o be exhaustive c u s s i o n , i t i s perhaps a p p r o p r i a t e  to present  i n this  dis-  a few s p e c i f i c  examples of i n t r a m o l e c u l a r a l k y l a t i o n s of s a t u r a t e d ketones. Examples of the l a t t e r can be found i n the s y n t h e s i s of most c l a s s e s o f n a t u r a l products  such as a l k a l o i d s ,  sesquiterpenes,  s t e r o i d s and t r i t e r p e n e s . In t h e i r t o t a l s y n t h e s i s o f ( ) - s e y c h e l l e n e , P i e r s e t a l  20  +  used as the c r i t i c a l step the i n t r a m o l e c u l a r c y c l i z a t i o n o f keto t o s y l a t e (45) t o g i v e norseychellanone dard methods was converted O  (45)  (46) which by s t a n -  i n t o (+)-seychellene (47).  (46)  (47)  -23-  Nagata's loid  group, i n t h e i r  astisine,  employed  synthesis  of the diterpene  an i n t r a m o l e c u l a r  cyclization  alka-  t o form  21 the  p r o p e r C/D  ring  system  In K e l l y ' s s y n t h e s i s tosylate  was  of  (±)-ishwarane  ( 4 9 ) upon b a s e t r e a t m e n t u n d e r w e n t  form t h e r e q u i r e d (50)  (48-M3)  converted  tetracyclic into  skeleton  (±)-ishwarane  (51) smooth  the keto cyclization  of ishwarane.  This  ( 5 1 ) by t h e B a r t o n  ketone  modifica-  TsO  synthesis  of  (±)-longifolene  (54),  u s e d as t h e c r i t i c a l  to  step  -24-  the r e q u i r e d  tricyclic  was s u b s e q u e n t l y  keto a l c o h o l  transformed  into  t h e p a s t two d e c a d e s numerous of  reaction  thetic  successfully  (53).  compound  ( + ) - l o n g i f o l e n e (54).  r e s e a r c h e r s have u s e d  and have t h u s  testified  In  this  type  t o i t s syn-  utility.  (B)  ex"(? -UNSATURATED ;  ALDEHYDES AND  The i n t r a m o l e c u l a r a l k y l a t i o n carbonyl  compounds h a s a l s o b e e n u s e d  the c o n s t r u c t i o n intramolecular reported  of p o l y c y c l i c  alkylations  involved  by t r e a t m e n t  droxide  t o form  KETONES of a $-unsaturated  as t h e key r e a c t i o n i n  compounds.  S e v e r a l examples o f  o f a^B-unsaturated ketones  and some a r e d i s c u s s e d b e l o w .  of m a a l i o l (55)  The l a t t e r  cyclization  o f the l a t t e r  the t r i c y c l i c  have  been  Thus B u c h i ' s s y n t h e s i s  o f a, B - u n s a t u r a t e d k e t o b r o m i d e w i t h m e t h a n o l i c p o t a s s i u m hy-  carbon  skeleton of maaliol  (56)  25 In t h e i r  s y n t h e s i s o f (•£)-aromadendrene  (59)  , Buchi e t a l  24  -25-  used s i m i l a r c o n d i t i o n s and c y c l i z e d bromide (57)  (55)  (56)  b i c y c l i c a g-unsaturated  aldehyde  was subsequently converted i n t o  the above examples,  t o the  (58).  The l a t t e r compound  (4)-aromadendrene  (59).  only gamma a l k y l a t i o n was r e a l i z e d ,  In  forming  a cyclopropyl derivative. Another example o f gamma a l k y l a t i o n of an k e t o n e , ' as the e x c l u s i v e p r o d u c t , i s of  cij8-unsaturated keto t o s y l a t e  i n t - b u t y l a l c o h o l at 4 0 ° f o r 1.5  a, g-unsaturated  shown below.  Thus, treatment  (60) w i t h potassium t - b u t o x i d e hours y i e l d e d the c y c l o p r o p y l  compound (61). Examples o f gamma a l k y l a t i o n o f an o^g-unsaturated  ketone  where a l l t h r e e modes o f c y c l i z a t i o n were t h e o r e t i c a l l y  possible  27 can a l s o be found i n the l i t e r a t u r e .  Thus, Bonet e t a l  v e r t e d the a,3 - u n s a t u r a t e d keto mesylate lated  a 3~unsaturated ketone (  methoxide i n methyl a l c o h o l . a,3-unsaturated ketone  con-  (62) i n t o the y - a l k y -  (63) by the a c t i o n o f sodium  In H a l p e r n s '  synthesis of  (63), the keto t o s y l a t e  (64) upon base  -27treatment underwent c y c l i z a t i o n which i n d i c a t e d t h a t  the l e a v i n g group  changing  from a mesylate t o a t o s y l a t e had no a f f e c t  on the p o s i t i o n o f c y c l i z a t i o n .  One f u r t h e r example where gamma 39  a l k y l a t i o n was the major process i s shown below treatment o f the a , 3 - u n s a t u r a t e d  keto t o s y l a t e  .  Thus,  (65) w i t h potassium  t - b u t o x i d e i n t - b u t y l a l c o h o l y i e l d e d the gamma a l k y l a t e d c t g -un;  saturated  ketone  (66) .  (65)  (66)  Examples o f i n t r a m o l e c u l a r  a l k y l a t i o n reactions  where a l l  three modes o f c y c l i z a t i o n were t h e o r e t i c a l l y p o s s i b l e b u t where i  -28-  the major product was  the product of a - a l k y l a t i o n have a l s o  29 been r e p o r t e d . mesylate  Thus, treatment of the a,B - u n s a t u r a t e d keto  (67) w i t h sodium h y d r i d e i n dimethoxyethane c o n t a i n i n g  some e t h a n o l y i e l d e d the t r i c y c l i c B ; Y - u n s a t u r a t e d ketone (68) 30 i n 60% y i e l d as the major product. Turner e t a l in their  approach  to a d i t e r p e n e a l k a l o i d s y n t h e s i s c y c l i z e d the a B -un(  s a t u r a t e d keto epoxide keto a l c o h o l  (69) t o the a a l k y l a t e d  B^Y-unsaturated  (70) by treatment of the former w i t h  t - b u t o x i d e i n t - b u t y l alcohol-benzene  (69)  potassium  f o r one hour a t 60°.  :  (70)  -29-  F i n a l l y , the work of C a r g i l l e t a l f e a s i b i l i t y of • a " - a l k y l a t i o n  i l l u s t r a t e d the  i n a v a r i e t y o f c^B -unsaturated  ketones where a and y a l k y l a t i o n s were a l s o t h e o r e t i c a l l y possible.  Thus treatment of the a,3-unsaturated keto bromides Br  (73)  (71),  (72) and (73) w i t h potassium t - b u t o x i d e i n  t-butyl  -30-  alcohol  yielded  The  the  corresponding products of  examples o f  intramolecular  alkylations  c a r b o n y l compounds t h a t have been d i s c u s s e d illustrated modes o f  clearly  t h a t the  cyclization  are  found.  c a s e s , where s e v e r a l  selectively tion  or  •III.  lar of  for  y  some c a s e s ,  alkylation  the  was  alkylation  But,  as  d e t e r m i n e i f the controlled  by  tention  carry  to  ated ketones the (X)  s i t e of  out  (77a  reaction  mode o f  the  X=C1,  reaction  the  77b  e f f o r t to  X=I)  and  to and  s u c h as  o b s e r v e any  b e e n done  alkylation  conditions. to  s i t e of  intention  parameters  can  I t was  determine,  alkylation.  synthesize (95  X=OSCH ) ,  0  X=C1  possible,  ;  and  to  and  leaving  J  base, s o l v e n t  change i n p o s i t i o n  (95)  in-  a ft - u n s a t u r -  ,X  X=I.  our  More  the  q  to  be  if  alkylation.  (77a) (77b)  Products  have b e e n  d e f i n i t i v e s t u d y has  such a study  our  reaction  intramolecular  controlled  i t was  i n an  no  posi-  intramolecu-  (  yet  varying  which parameters specifically  of  gamma  of . a 3-unsaturated ketones.  possible  In  observed.  l i t e r a t u r e i s s p o t t e d w i t h examples of  realized.  structural  seemed.possible,  alpha p o s i t i o n ,  where  have  theoretical  realized.  The  theoretically  section  the  PROBLEM  reactions  ;  in this  THE  every  group  at  alpha prime p o s i t i o n  alkylation  vary  In  s i t e s of  alkylation  a B-unsaturated  of  p r o d u c t s from a l l t h r e e  f e a t u r e s were s u c h t h a t o n l y other  a"alkylation.  X=0S-CH  3  of  -31-  DISCUSSION I.  PREPARATION OF 4 a-(3-CHLOROPROPYL)-4,4a,5,6,7,8— HEXAHYDRO-2-( 3H) -NAP HT HALE NONE (77a) and 4a- ( 3-IODOPROPYL)— 4, 4a, 5,6 , 7, 8-HEXAHYDRO-2-( 3H)-NAPHTHALENONE (77b) : The requisite a, 3-unsaturated keto chloride and iodide  (77a,b) were readily prepared from cyclohexanone via an eight step sequence as outlined, in Scheme II. Conversion of cyclo-  (77a) X=C1 (77b) X=I  hexanone into the corresponding pyrrolidine enamine (79) was 32 accomplished according to the procedure of G. Stork  . Treat-  ment of the crude pyrrolidine enamine (79) with allyl bromide in refluxing acetonitrile, followed by hydrolysis of the resultant product with aqueous methyl alcohol yielded 2-allylcyclohexanone (80) in 60% yield.  The conversion is shown below. Compound (80)  was allowed to react with methyl vinyl ketone according to the 33 procedure of Marshall  . Thus treatment of 2-allylcyclohexanone  with methyl vinyl ketone in the presence of a catalytic amount of 3N sodium methoxide, under an atmosphere of nitrogen, and maintaining the reaction temperature at -10° C for 24 hours,  -32-  -33-  afforded  a'mixture  o f two p r o d u c t s , the g-hydroxy ketone (81)  and the d e s i r e d a 8 - u n s a t u r a t e d ketone ;  (82). The k e t o l  converted i n t o the d e s i r e d a ; B -unsaturated ketone  (82) by  treatment w i t h sodium methoxide i n r e f l u x i n g methyl 2 hours.  The o c t a l o n e  (81) was  alcohol for  (82) was allowed t o r e a c t w i t h e t h y l e n e  •OH  (80)  (82)  g l y c o l i n r e f l u x i n g benzene c o n t a i n i n g p-toluenesulfonic spectral  (81)  a c a t a l y t i c amount o f  a c i d t o a f f o r d the e t h y l e n e k e t a l  (83). The  data o b t a i n e d from the l a t t e r compound was i n complete  0 (82)  accord with trum  (83)  the a s s i g n e d s t r u c t u r e .  showed no  a b s o r p t i o n due  o b s e r v a t i o n w h i c h was magnetic of  resonance  four o l e f i n i c  the  (^"H  four protons  with  ketal  formation. indicated  the presence  a t . 6-3.7, w h i c h of the k e t a l H  spec-  The  the  an  proton  presence  of four equivalent  c o u l d be  readily  functionality.  attributed  Although  the  H Z.H  0  spectral  and  the i n f r a r e d  to a carbonyl f u n c t i o n a l i t y ,  N.M.R.) s p e c t r u m  protons  methylene protons, to  in line  Thus,  0  data c o u l d not d i a g n o s t i c a l l y  prove  that  the  double  -35-  bond had  i n f a c t migrated  i s w r i t t e n as-such  during k e t a l i z a t i o n  s i n c e i t i s w e l l known t h a t d u r i n g  formation of an e t h y l e n e k e t a l of an having  gamma p r o t o n s ,  conjugation intermediates  .  ; the s t r u c t u r e  a B-unsaturated ;  the double bond w i l l  the ketone,  i s o m e r i z e out of  S p e c t r a l data d e r i v e d from subsequent s y n t h e t i c (see below) confirmed  this  assignment. 40  Ethylene k e t a l  (83) was  s u b j e c t e d to hydroboratxon  , using  a dimethylsulfide-borane  complex as the borane source.  r e a c t i o n was  a t room temperature f o r a p e r i o d of  done i n THF  The  - 3 6 -  2 hours.  At this  time  composed b y t r e a t m e n t the k e t a l  t h e i n t e r m e d i a t e a l k y l b o r a n e was d e with  N.M.R. s p e c t r u m  a broad  h y d r o g e n peroxide t o a f f o r d  a l c o h o l ( 8 4 ) . The i n f r a r e d  pound showed t h e p r e s e n c e The  alkaline  multiplet  the v i n y l p r o t o n .  spectrum  remained  was p a r t i c u l a r l y  proton  This last  result  confirmed  m u l t i p l e t which i s t y p i c a l Other  singlet at  then  on t h e c a r b o n  (2H) entered C  and n o t a  adjacent  t o other  included a  a t 6=3.6 a t t r i b u t e d  atom b e a r i n g t h e h y d r o x y l  to the  OMs  (85)  k e t a l a l c o h o l (84)  crystalline  Also  group.  OH  (84)  the  the v i n y l  as a s i n g l e t  o f a v i n y l proton  bond  (£=4.0,due t o t h e f o u r e t h y l e n e k e t a l p r o t o n s .  ,  The  t h a t the double  f e a t u r e s i n t h e ^"H N.M.R. s p e c t r u m  p r e s e n t was a m u l t i p l e t protons  attributed to  I f the double  t o t h e k e t a l moiety  a b s o r p t i o n w o u l d have a p p e a r e d  protons.  informative, exhibiting  (IH) c e n t e r e d a t 6=5.4 r e a d i l y  conjugated  com-  o f a n a l c o h o l a b s o r p t i o n a t 34 50 c m " \  bond h a d i s o m e r i z e d d u r i n g k e t a l i z a t i o n . had  o f the l a t t e r  was q u a n t i t a t i v e l y  k e t a l mesylate  with methanesulfonyl  chloride  (85)  converted  by t r e a t m e n t  into  o f t h e former  and t r i e t h y l a m i n e i n methylene  -37-  c h l o r i d e a t 0°C f o r f o r t y - f i v e minutes. The H N.M.R. spec1  trum of the e t h y l e n e k e t a l mesylate  (85) showed a broad  p l e t centered a t 6=5.5 due t o the v i n y l proton.  multi-  A multiplet  centered a t 6=4.3 c o u l d be a t t r i b u t e d t o the two protons on the carbon b e a r i n g the mesylate  group.  Additional  spectrum were the s i g n a l s due t o the mesylate at  6=3.0, and the e t h y l e n e k e t a l protons  f e a t u r e s o f the methyl  protons  a t 6=3.8.  OMs  GI  (85)  (86)  Treatment o f the mesylate  ketal  (85) w i t h 5 e q u i v a l e n t s o f  l i t h i u m c h l o r i d e i n r e f l u x i n g acetone  overnight afforded  y i e l d , a f t e r workup, the e t h y l e n e k e t a l c h l o r i d e  (86) .  i n 94% The "*"H  N.M.R. spectrum showed a broad m u l t i p l e t centered at 6 =5.48 due t o the v i n y l p r o t o n .  A s i n g l e t at 6 =3.9 8 a t t r i b u t e d t o the  f o u r e t h y l e n e k e t a l protons,  and a m u l t i p l e t c e n t e r e d a t 6 =3.5  a s s i g n e d t o the two protons on the carbon b e a r i n g the c h l o r i n e atom.  The above data, combined w i t h the absence o f a s i n g l e t  due t o the mesylate posed s t r u c t u r e  methyl protons were i n accord w i t h the pro-  f o r the e t h y l e n e k e t a l c h l o r i d e (86).  -38-  Acid  hydrolysis  of the ethylene k e t a l  aqueous s u l f u r i c a c i d  in refluxing  s a t u r a t e d ketone c h l o r i d e from  the a l c o h o l .  presence 1660  at was  T h i s was  functionality.  6=5.75 due now  infrared  o f an a - u n s a t u r a t e d  cm"^.  ketal  The  (77a), as  to lower  using  a f f o r d e d t h e ct 8 -un;  a y e l l o w o i l i n 90% of  the  loss  "*"H N.M.R. s p e c t r u m  field  (86)  (77a)  showed  yield the  ketone carbonyl a b s o r p t i o n at  t o the v i n y l p r o t o n .  shifted  acetone  spectrum  i n accord with The  chloride  The  of the  ethylene  showed a  v i n y l proton  singlet absorption  compared t o t h e v i n y l p r o t o n  ab-  -39s o r p t i o n o f the e t h y l e n e k e t a l c h l o r i d e lower  field  carbon  had  The s h i f t t o  i s due t o the d e s h i e l d i n g e f f e c t o f the  double  confirmed,  (86).  bond and the c a r b o n y l moiety.  t h a t , as expected,  carbon-  These r e s u l t s  the carbon-carbon  double  bond  i s o m e r i z e d back i n t o c o n j u g a t i o n with the c a r b o n y l group. Had  the double  tiplicity  bond remained out o f c o n j u g a t i o n the mul-  o f the s i g n a l due t o the v i n y l proton would not be a  s i n g l e t but r a t h e r a m u l t i p l e t s i n c e i t would remain a d j a c e n t to  other  protons.  Treatment o f the e t h y l e n e k e t a l mesylate  (85) w i t h  e q u i v a l e n t s o f sodium i o d i d e i n r e f l u x i n g acetone e t h y l e n e k e t a l i o d i d e (87).  five  afford  the  The H N.M.R. spectrum showed a 1  broad m u l t i p l e t c e n t e r e d a t 6=5.4 due t o the v i n y l p r o t o n , a s i n g l e t c e n t e r e d a t 6=3.9 a t t r i b u t e d t o the f o u r e t h y l e n e p r o t o n s , and a m u l t i p l e t protons  on the carbon  ketal  centered at 6=3.2 a s s i g n e d t o the two  b e a r i n g the i o d i n e atom.  The above data  combined w i t h the absence o f a s i n g l e t due t o the  mesylate  methyl protons, ethylene ketal Acid  confirmed  t h a t the proposed  i o d i d e was a s w r i t t e n f o r compound ( 8 7 ) .  h y d r o l y s i s of the ethylene  aqueous s u l f u r i c  acid  i nrefluxing  u s u a l workup, t h e a , g - u n s a t u r a t e d crystalline The  ketal  acetone  of this  compound  ^<5-=3.2 a t t r i b u t e d  proton,  from  the a l c o h o l  showed a s i n g l e t a t  and a m u l t i p l e t  t o t h e two p r o t o n s  The i n f r a r e d  ot^ 8 - u n s a t u r a t e d  posed  (77b) a s a w h i t e  (77b)  ,6=5.7 due t o t h e v i n y l  spectrum  (87) u s i n g  afforded, after the  ketone i o d i d e  (87)  atom.  iodide  (m.p. 60-61°c)in 30% y i e l d  compound  "*"H N.M.R. s p e c t r u m  iodine  structure f o r the  spectrum  centered a t  on t h e carbon  showed t h e p r e s e n c e  c a r b o n y l a b s o r p t i o n a t 1655 cm~^.  and ^"H N.M.R. s p e c t r u m  were i n a c c o r d w i t h  s t r u c t u r e f o r t h e ot,g-unsaturated  The  data  confirms  t h a t , as expected,  had  i s o m e r i z e d back  into  bearing the  The i n f r a r e d the pro-  ketone i o d i d e  t h e carbon-carbon  conjugation with  o f an  the carbonyl  (77b) . double group.  -41-  I I . INTRAMOLECULAR GENERAL  (A)  The  ALKYLATION  STUDY  CONSIDERATIONS:  octalone  (77a) was s u b j e c t e d t o a v a r i e t y o f  a l k y l a t i o n r e a c t i o n c o n d i t i o n s i n an e f f o r t t o determine what parameters, i f any, c o n t r o l l e d the p o s i t i o n o f c y c l i z a t i o n . These r e s u l t s are summarized i n Table I .  Cl  0 (77a)  The  g e n e r a l procedure used i n t h i s study was as f o l l o w s .  To begin w i t h , of o c t a l o n e prepared  a l l r e a c t i o n s were c a r r i e d out u s i n g 1.0 mmol  (77a).  Two e q u i v a l e n t s  (2.0 mmol ) o f base were  under an atmosphere o f n i t r o g e n i n a three neck  which had been p r e v i o u s l y flame d r i e d , by adding potassium  metal t o t - b u t y l a l c o h o l .  potassium  t-butoxide  flask  2.0 mmol  of  When the base used was  and any s o l v e n t other than t - b u t y l a l c o h o l  was employed the t - b u t y l a l c o h o l was d i s t i l l e d and r e s i d u a l s o l v e n t removed under reduced t-butoxide  as a white powder.  pressure  potassium  The a p p r o p r i a t e s o l v e n t was  then added t o the anhydrous potassium A s o l u t i o n o f the o c t a l o n e  to afford  t-butoxide.  (77a) (1.0 mmol ) i n the r e q u i r e d  -42-  s o l v e n t was subsequently added dropwise a t room temperature and the  r e a c t i o n mixture was l e f t  erature  f o r the r e q u i r e d  t o s t i r a t the a p p r o p r i a t e  length  o f time.  temp-  I f the r e a c t i o n  solvent  was  t - b u t y l a l c o h o l , the i n i t i a l l y employed t - b u t y l  alcohol  was  n o t removed and the u s u a l r e a c t i o n procedure was f o l l o w e d .  The  volume o f s o l v e n t  used was the same f o r each run (40 m l ) .  When l i t h i u m t-butoxide was the base used, i t was formed by  adding two e q u i v a l e n t s  ml  of t-butyl alcohol.  of o c t a l o n e If by  (2.0 mmol )of n - b u t y l l i t h i u m t o 20 T h i s was f o l l o w e d  (77a) i n 20 ml o f t - b u t y l  lithium diisopropylamide  by dropwise  alcohol.  was t h e base, i t was prepared  t r e a t i n g a 1:1 mixture o f d i i s o p r o p y l a m i n e  (2.0 mmol ) s o l u t i o n lithium  addition  (THF), w i t h 2 e q u i v a l e n t s  (2.0 mmol ) : HMPA* o f methyl  (2.0 mmol-).  A f t e r the r e q u i r e d  l e n g t h o f time f o r the r e a c t i o n  t o be  complete, the r e a c t i o n mixtures were quenched by p o u r i n g them i n t o 0.1 N h y d r o c h l o r i c extracted  with ether.**  a c i d and t h e r e s u l t a n t mixture was The e t h e r e x t r a c t s were combined and  washed w i t h water and b r i n e  u n t i l n e u t r a l , d r i e d over magnesium  s u l f a t e and evaporated t o y i e l d a crude o i l .  An e t h e r s o l u t i o n  o f t h i s crude o i l was i n j e c t e d i n t o a gas chromatograph t o determine the product  ratios.  At t h i s time one e q u i v a l e n t compound, p r e v i o u s l y  (1.0 mmol ) o f a standard  shown t o have an equal thermal  * HMPA - hexamethylphosphoramide **When HMPA was s o l v e n t , Pet. e t h e r was employed f o r  conductivity  extraction.  -43-  molar  response, a t the temperature  the crude r e a c t i o n m i x t u r e .  of a n a l y s i s , was added t o  A s o l u t i o n o f the mixture was then  i n j e c t e d i n t o a gas chromatograph t o determine yield.  the G.L.C.  In s i m p l e r terms the l a s t sentence can be expressed  i n the f o l l o w i n g way.  I f one m i l l i m o l e o f a c e r t a i n  compound  i s combined w i t h one m i l l i m o l e of another compound t h a t has a thermal c o n d u c t i v i t y i d e n t i c a l t o the f i r s t and t h i s mixture i s d i s s o l v e d i n a s o l v e n t and i n j e c t e d i n t o a gas  chromatograph,  then the r e s p e c t i v e peaks should be o f equal a r e a . is,  This r e s u l t  o f course, dependent on the f a c t t h a t both compounds have  the same thermal c o n d u c t i v i t y molar response chromatograph d e t e c t o r a t the temperature was t a k e n .  To determine  f o r the gas  t h a t the chromatogram  a G.L.C. y i e l d , one simply expresses  the area of the product peak as a percentage o f the area o f the standard peak.  That i s t o say, i f the r e a c t i o n i s q u a n t i -  t a t i v e one would expect t h a t both peaks should be o f e q u a l area and hence, expressed as a percentage the y i e l d would be 100%. The  e n t i r e a n a l y s i s mixture was then d i s t i l l e d  duced p r e s s u r e and weighed.  under r e -  The i s o l a t e d y i e l d was then de-  termined by s u b t r a c t i n g the weight o f the standard compound added from the t o t a l d i s t i l l e d weight t o g i v e the r e a l weight of product formed. assumption  I m p l i c i t i n t h i s a n a l y s i s procedure was the  t h a t a l l o f the standard compound was  T h i s i s not a poor assumption  s i n c e the temperature  the standard compound d i s t i l l e d was s l i g h t l y temperature  distilled.  a t which the product  distilled.  a t which  lower than the  All  the r e a c t i o n s were done i n d u p l i c a t e and the numbers  i n the t a b l e s r e p r e s e n t an average  v a l u e f o r the r a t i o s .  The  l i s t e d v a l u e s showed a v a r i a t i o n of«^^% from the i n d i v i d u a l experimental values. to  When the r e a c t i o n products were exposed  the same r e a c t i o n and workup c o n d i t i o n s as o c t a l o n e (77a)  they were r e c o v e r e d unchanged.  T h i s l a t t e r work i n s u r e d t h a t  the product r a t i o s o b t a i n e d were r e a l r e p r e s e n t a t i o n s o f i n t r a m o l e c u l a r a l k y l a t i o n s and not the r e s u l t o f a rearrangement of one o r more o f the p r o d u c t s . • (B)  INTRAMOLECULAR ALKYLATIONS  INVOLVING  4a-(3-CHL0R0-  PROPYL) -4, 4a, 5, 6 ,7, 8-HEXAHYDRO-2-( 3H) -NAPHTHALENONE (77a) 1.  General  Under the normal c o n d i t i o n s f o r g e n e r a t i n g the thermodynamic e n o l a t e anion  (88), u s i n g potassium-t-butoxide i n  t - b u t y l a l c o h o l , one would expect c y c l i z a t i o n t o occur a t the a o r Y p o s i t i o n s and not a t the a p p o s i t i o n , p r o v i d e d o f course t h a t a l k y l a t i o n of the i n i t i a l l y  formed d i e n o l a t e anion (89)  i s much slower than e q u i l i b r a t i o n  (rate-1^ rate3).  B e f o r e u n d e r t a k i n g t h i s study we c o n s i d e r e d the f o l l o w i n g parameters to be p o t e n t i a l l y i n f l u e n t i a l i n determining the p o s i t i o n of c y c l i z a t i o n .  These f a c t o r s were s o l v e n t , base,  c a t i o n , temperature  and c a t i o n complexing  o t h e r hand, we f e l t  t h a t the e f f e c t o f r e a c t a n t c o n c e n t r a t i o n s  would have minimal in  agents.'  i n f l u e n c e on the product r a t i o s .  On the  The r e s u l t s  Table I c l e a r l y demonstrate t h a t the above p r e l i m i n a r y ex-  p e c t a t i o n s were i n f a c t  fulfilled.  -45-  SCHEME  III  -46-  2.  Effect  of Solvent  The  octalone  (77a) was s u b j e c t e d t o r e a c t i o n  t i o n s where t h e t h e r m o d y n a m i c e n o l a t e treatment butyl  of octalone  alcohol  f o r m a t i o n o f two p r o d u c t s (entry  I, Table  1)•  ( / &; 8 8 / 1 2 ) * i n 78% i s o l a t e d a  This result  i s i n accord with  that  to the r i g h t  d i e n o l a t e anion  necessary. THF  i s an a p r o t i c  ibration shift in  Since t-butyl  t o occur  i n THF.  alcohol  (88), a p r o t o n  i s a protic  s o l v e n t one w o u l d e x p e c t i n t-butyl  alcohol  Thus t h e r e a c t i o n  2 equivalents  i n THF a t room t e m p e r a t u r e isolated  decreased  and, i n f a c t ,  * representing the product The m o l e r a t i o s e n t e d by / a a y  o f compound  equil-  equilibration  When o c t a l o n e ) of potassium  of  a  a  / a  t-butoxide  / " ' h a d , as e x p e c t e d , a  r e v e r s e d from  as /  (77a) was  alkylated material  a ratio  indicates  (90) t o compound  y  (90)  source i s  solvent, while  and a m i n i m a l  The r a t i o  ratio  to s h i f t  a thermodynamic  f o r f o u r hours,  almost  yield  i n THF s h o u l d show a d e c r e a s e  (2.0 mmol  i n 70% y i e l d .  i n the  scheme I I I .  f o rthe equilibrium  t h e amount o f a a l k y l a t e d p r o d u c t .  treated with  was  i n order  Thus  t-butoxide i n t —  f o r four hours r e s u l t e d  Scheme I I I i n d i c a t e s t o form  (88) was g e n e r a t e d .  (77a) w i t h p o t a s s i u m  a t room t e m p e r a t u r e  condi-  (91)  o f 88/12  the following:  (91) i s r e p r e -  -47-  observed i n t - b u t y l a l c o h o l to a r a t i o of 15/85 THF.  The  crease it  observed i n  e f f e c t of an a p r o t i c s o l v e n t such as THF  the l i f e  time of d i e n o l a t e anion  to a l k y l a t e b e f o r e  (89)  was  to i n -  sufficiently  for  i t equilibrated.  HMPA, an a p r o t i c s o l v e n t , has  been shown to s o l v a t e  cations  35 such as potassium i o n should  increase  octalone t-butoxide  (77a)  .  T h i s s o l v a t i n g a b i l i t y of HMPA  the r e a c t i v i t y of a n i o n s . w i t h two  equivalents  Thus treatment o f  (2.0 mmol ) of potassium  i n HMPA f o r 15 minutes a f f o r d e d a mixture of a ' and  a - a l k y l a t e d p r o d u c t s i n the r a t i o of 81/19.  This r e s u l t i s i n  accord w i t h Scheme I I I where e q u i l i b r a t i o n of the formed d i e n o l a t e (rate_2^rate3) p r o d u c t than  anion  (89) was  f a s t e r than a l k y l a t i o n  r e s u l t i n g i n a higher (^alkylated product.  r e s u l t w i t h the  r e s u l t obtained  s t u d i e d , namely THF,  proportion  the thermodynamic e n o l a t e  When comparing t h i s  i n the other  complexing a b i l i t y  anion  (88)  i s f a s t e r than the  rate  (89) i . e . of  f o r c a t i o n s found when HMPA i s employed  i s a general  f e a t u r e observed i n other types of 35  r e a c t i o n s done i n HMPA where i o n p a i r s are 3.  aprotic solvent  T h i s enhanced r e a c t i v i t y i s a r e f l e c t i o n  as s o l v e n t , and  latter  t h a t the r a t e o f a l k y l a t i o n of  of a l k y l a t i o n o f the k i n e t i c d i e n o l a t e anion  the  of a a l k y l a t e d  i t i s c l e a r t h a t the o v e r a l l r a t e of a l -  k y l a t i o n i s f a s t e r i n HMPA and  rate4^rate3.  initially  involved.  E f f e c t of Base  In the above s e c t i o n s o l v e n t was potassium t-butoxide  was  the v a r i a b l e  always the base employed.  t a i n the e f f e c t of base we  a l s o considered  lithium  To  and ascer-  t-butoxide  -48-  and l i t h i u m d i i s o p r o p y l a m i d e .  When l i t h i u m t - b u t o x i d e was  employed as base i n t - b u t y l a l c o h o l (entry 6, T a b l e I) t h e r e was  no d i s c e r n a b l e r e a c t i o n a t room temperature  hour p e r i o d . w i t h potassium  When comparing t h i s r e s u l t t o the r e s u l t o b t a i n e d t - b u t o x i d e i n t - b u t y l a l c o h o l i t becomes c l e a r  t h a t the l i t h i u m d i e n o l a t e anion the potassium  a f t e r a 24  d i e n o l a t e anion  (89) i s much l e s s r e a c t i v e  (89).  than  T h i s no doubt i s a r e -  f l e c t i o n o f bond c h a r a c t e r , the lithium-oxygen bond having more c o v a l e n t c h a r a c t e r , thus " t i g h t e r " , than the potassium-oxygen bond which i s l e s s c o v a l e n t . However, r e f l u x i n g f o r s i x hours i n t - b u t y l a l c o h o l a f f o r d e d a mixture o f ot and ^ a l k y l a t e d products of 57/39 r e s p e c t i v e l y .  i n the r a t i o  T h i s r e s u l t i s i n accord w i t h Scheme I I I  where a l k y l a t i o n o f the i n i t i a l l y i s s l i g h t l y slower than  formed d i e n o l a t e anion (89)  equilibration.  As p r e v i o u s l y demonstrated, i t i s p o s s i b l e t o generate the k i n e t i c d i e n o l a t e anion  (89) under c o n d i t i o n s where i t s  i n t e g r i t y i s maintained by u s i n g l i t h i u m d i a l k y l a m i d e s as bases i n an a p r o t i c s o l v e n t .  Thus treatment o f o c t a l o n e (77a)  w i t h 2 e q u i v a l e n t s (2.0 mmol.) of a 1:1 mixture o f l i t h i u m d i i s o p r o p y l a m i d e : HMPA complex i n THF a t room temperature f o r 3 hours a f f o r d e d e x c l u s i v e l y , i n 55% i s o l a t e d y i e l d , the p r o duct o f a a l k y l a t i o n  (entry 7, T a b l e I ) .  This r e s u l t i s i n  a c c o r d w i t h Scheme I I I where a l k y l a t i o n i s much f a s t e r proton  transfer.  than  -49-  4.  E f f e c t of Complexing Agent -  The mmol :) o f  observed e f f e c t of  18-crown-6 t o  Firstly,  i t greatly  reaction  time necessary  from f o u r  hours to  effect tion the  of  to rate  of  minutes.  alcohol  (entry  to  alkylation. and  to  2,  I).  Table the  rate  the  I t i s not  95%  rate  material  of  the  of total  observed  of e q u i l i b r a (88)and  to  complexes w i t h anion  enhance the  uncomplexed  surprising that  of n u c l e o p h i l i c reactions  the  amount  The  anion  dienolate  fold.  starting  f r o m 88%  (2.0  decreasing  Secondly, the  increase  leaves  two  rate,  18-crown-6 e t h e r  t h u s more r e a c t i v e .  enhances the  reaction  thermodynamic d i e n o l a t e  potassium c a t i o n and  the  increased  18-crown-6 was  form the  equivalents  f o r disappearance of  fifteen  in t-butyl  a d d i n g two  r e a c t i o n medium was  enhanced  a a l k y l a t e d p r o d u c t was product  the  18-Crown-6  since  18-crown-6 t h i s type  of  36 b e h a v i o u r has  literature  When 18-crown-6 potassium the of  containing  (2.0  (2.0  the  d u c t f r o m an-  than an  four  Synthetic previously  (77a)  was  causing  increase of  containing  effect is of  2  virtually  equivalents  s o l u t i o n of octalone t-butoxide  completion of The  (77a)  showed an reaction  p r o d u c t r a t i o was  i n the  15/85  the  Thus a d d i t i o n  a THF  hours.  solution  (77a)  potassium  rate  a/^ratio  5.  octalone  mmol ) o f  showing  As  octalone  mmol ) t o  reaction  minutes r a t h e r affected  and  a THF  in t-butyl alcohol.  18-crown-6  ment o f  i s added t o  t-butoxide  same as  precedent.  enhancein  also  amount o f . a - a l k y l a t e d  to  15  pro-  35/62.  Application discussed,  (entry  3,  Table  1)  treated with potassium-t-butoxide  when i n THF  at  -50room temperature lation.  the major product was the one from  xx - a l k y -  T h i s i n d i c a t e d t h a t a l k y l a t i o n was f a s t e r than proton  transfer i n this solvent. a lower temperature alkylation.  I f the r e a c t i o n was c a r r i e d o u t a t  one might expect a decrease i n the r a t e o f  A l s o , by adding some t - b u t y l a l c o h o l t o t h i s THF  s o l u t i o n , thereby i n t r o d u c i n g equilibration  a good proton source, the r a t e of  (proton t r a n s f e r ) should i n c r e a s e  a d d i t i o n , i f an e q u i v a l e n t  even more.  In  o f 18-crown-6 e t h e r was added t o  t h i s t - b u t y l a l c o h o l - THF s o l u t i o n , e q u i l i b r a t i o n might be expected t o o c c u r s t i l l  faster.  Thus, the above mentioned c o n d i t i o n s 1.0 mmol  of octalone  of potassium  were combined and  (77a) was allowed t o r e a c t w i t h 2.0 mmol  t - b u t o x i d e i n a mixture o f t - b u t y l a l c o h o l - THF  (60/40) c o n t a i n i n g  2.0 mmol  o f 18-crown-6 a t -78°.  mixture was subsequently allowed t o warm up t o room with s t i r r i n g  f o r an a d d i t i o n a l 15 minutes.  The r e a c t i o n temperature  Under these  d i t i o n s none o f the . a - a l k y l a t e d p r o d u c t was o b t a i n e d .  con-  The  o n l y i d e n t i f i a b l e p r o d u c t i s o l a t e d was the p r o d u c t due t o a - a l k y l a t i o n accompanied by an u n i d e n t i f i e d compound i n the r a t i o o f 95:5. T h i s r e s u l t combined w i t h the r e s u l t o b t a i n e d  employing  l i t h i u m d i i s o p r o p y l a m i d e as base i n THF (entry 7, Table I) comp l i m e n t each o t h e r s y n t h e t i c a l l y . are  That i s t o say these r e s u l t s  s y n t h e t i c a l l y u s e f u l , i n t h a t i t i s now p o s s i b l e t o form  e i t h e r the product o f cx'alkylation o r the product o f . a - a l k y l a tion.  A t no time was t h e product o f y-alkylation  below f o r p r o o f ) .  d e t e c t e d (see  -Si-  te)  INTRAMOLECULAR ALKYLATIONS INVOLVING 4a-(3-IODO-  PROPYL )-4,4a,5,6,7, 8-HEXAHYDRO- 2-( 3H) -NAPHTHALENONE (77b) The effect of changing the leaving group was also studied and the results are recorded in Table I. When the leaving group was changed from chloride to iodide quite different results were obtained.  Since the rate of expulsion of a leaving  group X, (where x is a halide ion), decreases in the series I~^Br~^Cl~^F~, we felt that, a priori, iodide would be a "better" leaving group. We had anticipated that the reactions would occur faster and that more a'-alkylated product would be formed. That is to say, alkylation of the initially formed dienolate anion (91a) would be faster than equilibration.  0'  rp (92)  (91) SCHEME IV  +  [11 (90)  TABLE I - INTRAMOLECULAR ALKYLATION OF OCTALONE  (77aft)  -X  ENTRY  BASE  CI  1  K OBu  CI  2  K OBu  CI  3  K^Bu  Cl  4  K OBu  CI  5  K OBu  Cl  6  Li OBu  Cl  7  LDA,HMPA  Cl  8  K OBu  I  9  K OBu  I  10  K OBu  I  11  K OBu  ADDED REAGENT  fc  fc  t  18-Crown-6  18-Crown-6  fc  t  18-Crown-6  YIELD G.L.C. ISOLATED  RATIO OF PRODUCTS  78  12  88  72  71  5  95  4 h r . R.T.  74  70  85  15  4 hr.  R.T.  80  t-BuOH  15 min  R.T.  .  THF  15 min  R.T.  52  51.5  65  35  HMPA  15 min  R.T.  65  64  19  81  6 hr. r e f l u x  81  77  39  57  3 h r . R.T.  56  55  100  0  30 min 15 min  -78° R.T.  62  61  0  95  t-BuOH  15 min  R.T.  100  94  100  0  t-BuOH  15 min  R.T.  91.5  90  78  22  30 min 15 min  -7 8° R.T.  67  65  74  20  THF 18-Crown-6  REACTION CONDITIONS  t-BuOH  t-BuOH  fc  fc  SOLVENT  THF  fc  fc  OTHER  t-BuOH/THF 40/60  t-BuOH/THF 40/60  i  - a l l e n t r i e s done i n d u p l i c a t e . Unless stated otherwise, - products are stable to reaction conditions.  2 equivalents  J  o f base was employed.  I  -53-  Thus treatment of the i o d i d e d e r i v a t i v e , o c t a l o n e w i t h potassium t-butoxide  (77b),  i n t - b u t y l a l c o h o l at room tempera-  t u r e f o r 15 minutes r e s u l t e d i n the e x c l u s i v e formation product from was  a - a l k y l a t i o n i n 94%  isolated yield.  p r i s i n g , but  did eliminate  ments i n a p r o t i c s o l v e n t s k i n e t i c dienolate  anion  T h i s r e s u l t was  the  This r e s u l t  i n accord w i t h Scheme IV w i t h p r o t o n - t r a n s f e r  slow compared to a l k y l a t i o n .  of  being  not  too  very  sur-  the n e c e s s i t y of u n d e r t a k i n g e x p e r i such as THF.  (91a)  was  Since  a l k y l a t i o n of  much f a s t e r than proton  the  trans-  f e r even i n the presence of a l a r g e amount of p r o t i c s o l v e n t , ( t - b u t y l a l c o h o l ) , i t was  f e l t t h a t changing to an a p r o t i c  s o l v e n t would not p r o v i d e  a d d i t i o n a l s y n t h e t i c i n f o r m a t i o n as  t o the method of forming a - a l k y l a t e d  product.  What e f f e c t a complexing agent, such as 18-crown-6 would have on  the p r o d u c t r a t i o  v i o u s l y noted  a  / " ' ' was a  s t u d i e d next.  (above s e c t i o n ) , 18-crown-6 was  i n c r e a s e the r a t e o f e q u i l i b r a t i o n .  p e c t e d to a l t e r the r a t i o o f  t-butoxide lents  (77b)  addition ex-  a-alkylated  duct to perhaps form some a - a l k y l a t e d p r o d u c t . of o c t a l o n e  the  to  (77b), might be  -9 / ' from 100% a  pre-  observed  Therefore,  of 18-crown-6 to a s o l u t i o n o f o c t a l o n e  As  (1.0 mmol ) w i t h 2 e q u i v a l e n t s  pro-  Thus treatment o f potassium  (2.0 mmol ) i n t - b u t y l a l c o h o l c o n t a i n i n g  2 equiva-  (2.0 mmol •) of 18-crown-6 at room temperature f o r 15 min-  utes a f f o r d e d ,  i n 90%  i s o l a t e d y i e l d , a mixture of  k y l a t e d products i n a r a t i o of 22/78 (entry 10, expected, 18-crown-6 i n c r e a s e d thus decreased the amount of  a and  a' a l -  Table I ) .  the r a t e o f proton t r a n s f e r a-^alkylated product r e l a t i v e  the amount of '• a - a l k y l a t e d p r o d u c t .  As and to  -54-  (D)  SUMMARY OF INTRAMOLECULAR ALKYLATION STUDIES  S y n t h e t i c a l l y , these r e s u l t s are very s i g n i f i c a n t . have been able  We  t o form e x c l u s i v e l y the product o f a ^ - a l k y l a t i o n  i n 94% i s o l a t e d y i e l d under one s e t of r e a c t i o n c o n d i t i o n s , and the product of a - a l k y l a t i o n almost e x c l u s i v e l y y i e l d , under another s e t o f c o n d i t i o n s .  ()95%),  i n good  At no time was the  product of y - a l k y l a t i o n d e t e c t e d . The  foregoing  r e s u l t s have shown t h a t  c e r t a i n f a c t o r s are  important i n determining the p o s i t i o n o f i n t r a m o l e c u l a r t i o n o f a,$-unsaturated ketones. solvent, has  These f a c t o r s  alkyla-  include  c a t i o n , complexing agent, base and l e a v i n g group.  been c l e a r l y demonstrated when the s u b s t r a t e  (77a), t h a t i n a p r o t i c s o l v e n t ,  such as t - b u t y l  It  i s octalone alcohol,  the major product was the product of a a l k y l a t i o n , whereas i n an a p r o t i c s o l v e n t p r o d u c t of two  such as THF, the major product was the  a^alkylation.  differences  emerge.  When judging the e f f e c t o f c a t i o n , F i r s t l y , the potassium e n o l a t e i s much  more r e a c t i v e than the l i t h i u m e n o l a t e . e n o l a t e forms l e s s a - a l k y l a t e d than the potassium e n o l a t e The  Secondly, the l i t h i u m  product i n t - b u t y l  (compare entry  1 and 6, Table I ) .  e f f e c t of 18-crown-6 was t o i n c r e a s e  e q u i l i b r a t i o n as w e l l as t o i n c r e a s e kylation.  When 1 e q u i v a l e n t  alcohol  the r a t e o f  the o v e r a l l r a t e o f a l -  o f 18-Orown-6 was added t o the  r e a c t i o n mixture, whether i t was an a p r o t i c s o l v e n t a p r o t i c solvent  (t-BuOH) the r e s u l t was an i n c r e a s e  amount o-f a - a l k y l a t e d  (THF) o r i n the  product.  A d i r e c t comparison on how the l e a v i n g group a f f e c t s the  -55-  direction paring  of intramolecular cyclization  the r e s u l t s  i n entry  1, T a b l e  c a n be s e e n when com-  I to entry  10, T a b l e I .  One q u i c k l y n o t i c e s t h a t i o d i d e i s a much b e t t e r l e a v i n g g r o u p than  c h l o r i d e (see e q u a t i o n s  (E)  STRUCTURAL ASSIGNMENT The  lation, 88:12  products  compound  t-butoxide  of a-alkylation,  when o c t a l o n e  i n t-butyl  reaction products  using  silica  g e l packing  experimental).  PRODUCTS  compound  as a m i x t u r e  (9 0)  and a - a l k y -  i n a ratio of  77a was t r e a t e d w i t h  potassium  a l c o h o l a t room t e m p e r a t u r e f o r 4 h o u r s .  crude  to yield  OF ALKYLATION  ( 9 1 ) , were o b t a i n e d  respectively  mixture,  8 and 9) .  were s u b j e c t e d  t o column  and e l u t i n g w i t h  pure o c t a l o n e  chromotography,  a petroleum  (90) and p u r e  The  octalone  ether-ether (91) ( s e e  -56-  (91)  (90)  a'- PRODUCT The  a t 6 =5.55  to the v i n y l  in  (J=36hz) which  y-PRODUCT  carbonyl  (90) e x h i b i t e d a t r i p l e t  could  f  proton.  accord with  (92)  a-PRODUCT  ^"H N.M.R. s p e c t r u m o f o c t a l o n e  centered  urated  "  The i n f r a r e d  readily  spectrum  a b s o r p t i o n a t 1710 cm ^. the proposed  be a t t r i b u t e d  contained  T h e above d a t a i s  structure f o r octalone  N.M.R. s p e c t r u m o f t h e a - a l k y l a t e d p r o d u c t , showed a s i n g l e t to  the v i n y l  spectrum  proton  a t 167 0 cm \  be  of  could readily  to thecarbonyl  T h e above d a t a  ketone  group.  The i n f r a r e d carbonyl  i s i n accord with the  The s t r u c t u r e o f t h e p r o -  an a ^ - u n s a t u r a t e d  d i s t i n g u i s h e d from the product  saturated  be a s s i g n e d  (91) a s w e l l a s f o r o c t a l o n e  of y alkylation.  a-alkylation,  ( 9 0 ) . The  octalone (91),  o f an a 3 - u n s a t u r a t e d  structure f o r octalone  (92), the product duct  alpha  showed t h e p r e s e n c e  absorption proposed  a t 6=6.02 w h i c h  a sat-  ketone  (91) c o u l d  of y-alkylation,  (92) b y t h e f o l l o w i n g c h e m i c a l  a n a B -un-  sequence.  -57-  (90)  (92)  Thus, treatment of o c t a l o n e  (90)  under m o d i f i e d  Wolff-  37 Kishner carbonyl  reduction conditions  , to e f f e c t r e d u c t i o n of  group, u s i n g sodium g l y c o l a t e and  z i n e , a f f o r d e d the alkene hydrocarbon yield. centered  The  at 6 = 5.4 The  oxide-pyridine  i n f r a r e d spectrum c o n t a i n e d i n accord w i t h  (93) was  triplet the  no  carbonyl  the s t r u c t u r e  assigned  complex  then t r e a t e d w i t h a chromium t r i 38 ( C o l l i n s reagent)  6 hours to e f f e c t a l l y l i c  i s o l a t e d y i e l d , the product The  isolated  (93).  Hydrocarbon  for  i n 81%  which c o u l d r e a d i l y be a t t r i b u t e d to  a b s o r p t i o n which was compound  anhydrous hydra-  ^"H N.M.R. spectrum showed a w e l l r e s o l v e d  v i n y l proton.  to  (93)  the  o x i d a t i o n and  i n methylene c h l o r i d e form i n 85%  of ^ - a l k y l a t i o n , compound  *H N.M.R. spectrum of compound  (92) was  very  informative  e x h i b i t i n g a s i n g l e t a t 6=5.76 which c o u l d r e a d i l y be buted t o the v i n y l proton  adjacent  i n f r a r e d spectrum o f compound  (92)  (92).  attri-  t o the c a r b o n y l group. showed the presence of  The an  1670  cm  -1 H  1660  cm  §=6.02  t  H  6=5.76  (91)  rx 3  -1  (92)  - u n s a t u r a t e d ketone c a r b o n y l a b s o r p t i o n a t 1660 cm . x  D i r e c t comparison o f the s p e c t r a l data o b t a i n e d from compound ( 9 2 ) w i t h the s p e c t r a l data e x h i b i t e d by compound n o s t i c a l l y proved  (91) d i a g -  t h a t the a,3 -unsaturated ketone o b t a i n e d , i n  the above i n t r a m o l e c u l a r a l k y l a t i o n study, was i n f a c t the p r o duct o f a - a l k y l a t i o n and not the product o f y - a l k y l a t i o n . I I I . PREPARATION OF 4a-(MESYLATE METHYL)-4,4a,5,6,7,8-HEXAHYDRQ- 2-( 3H) -NAPHTHALFNONE (95) The  r e s u l t s o b t a i n e d from the above study,  ( s e c t i o n B and  C), c l e a r l y i n d i c a t e d t h a t the p o s i t i o n a t which i n t r a m o l e c u l a r a l k y l a t i o n of compounds  (77a) and (77b) had o c c u r r e d was de-  pendent on a number o f parameters.  One f u r t h e r v a r i a b l e we  wished t o e x p l o r e was the e f f e c t o f r i n g s i z e .  By v a r y i n g the  s i d e c h a i n l e n g t h as  i n compound (96),the s i z e  formed would be e f f e c t i v e l y  study r e q u i r e d the s y n t h e s i s  altered.  of compound  The r e q u i s i t e a , B - u n s a t u r a t e d r e a d i l y prepared from 2-(3H)-naphthalenone latter  The f i r s t  of the  ring  stage of  this  (95).  keto mesylate  (95)  was  4a-(carbomethoxy)-4,4a,5,6,7,8-hexahydro  (97)  as o u t l i n e d i n the scheme below.  The  compound was allowed to r e a c t w i t h e t h y l e n e g l y c o l i n  benzene c o n t a i n i n g a c a t a l y t i c  amount of  p-toluenesulfonic  -60-  COOCH.  COOCH.  pTsOH  (97.)  .OMs MsCl Et N 3  CH C1 2  H  2  2  " 0  4 2° Acetone  S 0  / H  DMs  (•95)  acid.  The m i x t u r e  overnight  to yield  data  obtained  from  with  the assigned  was r e f l u x e d , u s i n g a D e a n - S t a r k the ethylene ketal the l a t t e r structure.  ester  ( 9 8 ) . The s p e c t r a l  compound was i n c o m p l e t e Thus, t h e - i n f r a r e d  showed no a b s o r p t i o n due t o an e ^ g - u n s a t u r a t e d tionality, The  indicated  the presence  accord  spectrum  carbonyl  an o b s e r v a t i o n w h i c h was i n l i n e w i t h  ^"H N.M.R. s p e c t r u m  apparatus,  ketal  funcformation.  o f a broad mul-  -61-  tiplet,  centered  a t 6 = 5.7  compound  (98).  singlets  a t 6 = 4.0  readily  Other  attributed  features o f the  and.6 = 3.7.  attributed  t o the v i n y l  proton i n  N.M.R. s p e c t r u m were  The l a t t e r  t o the three protons  signal  c o u l d be  o f the methyl e s t e r  group and the former t o the f o u r e q u i v a l e n t e t h y l e n e  ketal  pro-  tons . The  ethylene  ketal  ester  conditions,  using  temperature  f o r 1 hour.  ketal m.p.  alcohol  absorption was  After  The i n f r a r e d  a t 3500 cm ^.  confirmed  aluminum h y d r i d e  the  spectrum  The l o s s  signals  compound  showed a t y p i c a l  o f the e s t e r carbonyl  hydroxyl group  by t h e l a c k o f an a b s o r p t i o n a t 1720 cm~^. T h e  attributed  hydroxyl  i n THF a t room  t h e u s u a l workup p r o c e d u r e , t h e  "'"H N.M.R. s p e c t r u m showed a s h a r p be r e a d i l y  to reduction  (99) was o b t a i n e d a s a w h i t e c r y s t a l l i n e  89-91°C. ''" 4  lithium  (98) was s u b j e c t e d  group.  singlet  t o t h e two p r o t o n s  a t 5=3.25, w h i c h on t h e c a r b o n  could  bearing  A d d i t i o n a l f e a t u r e s o f t h e s p e c t r u m were  a t 6=5.1 a n d 6=3.6.  T h e f o r m e r a b s o r p t i o n was due t o  -62-  (98)  the  -(99)  v i n y l proton  attributed  The ketal  to  ketal  mesylate  and  the  the  four  alcohol (100)  l a t t e r s i n g l e t c o u l d be  ethylene ketal  (99) (m.p.  was  methylene of  the  at  ethylene ketal  centered tered  chloride  at  a t .6 = 5.6  due  4=4.2 c o u l d  0°  be  into  1 0 2 - 1 0 2 . 5 ° C ) by  for  1 hour.  mesylate to  protons.  converted  former with methanesulfony1 c h l o r i d e  the  (100)  and  the  crystalline  treatment of  triethylamine  The  to  the  the in  ^"H N.M.R. s p e c t r u m  showed a b r o a d  v i n y l proton.  attributed  readily  multiplet  A multiplet two  protons  on  centhe  carbon b e a r i n g the mesylate group. spectrum at  included  signals  using  hydrolysis  the d e s i r e d  as a w h i t e spectrum  protons  p r o t o n s a t 6=3.85.  o f compound  acid  i nrefluxing  acetone o v e r n i g h t ,  a ^ - u n s a t u r a t e d k e t o n e m e s y l a t e (95)  crystalline  s a t u r a t e d ketone  of the  o f t h e e t h y l e n e k e t a l m e s y l a t e (100)  aqueous s u l f u r i c  afforded  features  due t o t h e m e s y l a t e m e t h y l  6=3.0 a n d t h e e t h y l e n e k e t a l  Acid  Additional  compound m.p. 9 8 - 9 9 ° C .  The i n f r a r e d  (95) showed t h e p r e s e n c e o f an a,£-unThis  obser  v a t i o n was i n a c c o r d w i t h t h e l o s s o f t h e e t h y l e n e k e t a l  func-  tionality.  The  carbonyl absorption  N.M.R. s p e c t r u m  a t 1670 cm  showed a s i n g l e t  due t o t h e t h r e e m e t h y l p r o t o n s o f t h e m e s y l a t e singlet  a t .6=4.33 c o u l d be r e a d i l y  attributed  group.  A  t o t h e two p r o -  t o n s on t h e c a r b o n b e a r i n g t h e m e s y l a t e g r o u p . "*"H N.M.R. showed t h e p r e s e n c e o f a b r o a d s i n g l e t to the v i n y l  at6=3.0  Lastly, the at;.6 = 5.8 due  p r o t o n a d j a c e n t t o the c a r b o n y l group.  -64-  IV. INTRAMOLECULAR ALKYLATION STUDY INVOLVING 4a-(MESYLATE METHYL)- 4,48,5,6,7, 8-HEXAHYDRO-2-j3H) -NAPHTHALENONE (95) (A)  GENERAL COMMENTS Octalone  (95) was s u b j e c t e d t o a v a r i e t y o f a l k y l a t i o n  c o n d i t i o n s i n an attempt t o determine what parameters the  p o s i t i o n of a l k y l a t i o n .  These  controlled  r e s u l t s are summarized  i n T a b l e I I . The g e n e r a l procedure used i n t h i s study was as follows.  F i r s t o f a l l , the r e a c t i o n s were c a r r i e d out u s i n g  195)'  1.0 mmol  o f o c t a l o n e (95). Two e q u i v a l e n t s (2.0 mmol ) of  base were prepared by adding to  t-butyl alcohol.  (2.0 mmol' ) o f potassium metal  T h i s procedure was c a r r i e d out under an  atmosphere o f n i t r o g e n i n a t h r e e neck f l a s k which had been p r e v i o u s l y flame d r i e d .  When the base used was potassium t —  b u t o x i d e and any s o l v e n t o t h e r than t - b u t y l a l c o h o l was emp l o y e d , the t - b u t y l a l c o h o l was d i s t i l l e d  and the r e s i d u a l  s o l v e n t removed under reduced p r e s s u r e t o a f f o r d potassium t — b u t o x i d e as a white powder. added t o the anhydrous  The a p p r o p r i a t e s o l v e n t was then  potassium t - b u t o x i d e .  -65-  A s o l u t i o n o f the o c t a l o n e  (95) (1.0 mmol ) i n the r e q u i r e d  s o l v e n t was subsequently added dropwise a t room temperature and the r e a c t i o n mixture was l e f t t o - s t i r a t the a p p r o p r i a t e erature  f o r the r e q u i r e d  length  o f time.  medium was t - b u t y l a l c o h o l , the i n i t i a l l y  temp-  When the r e a c t i o n employed  t-butyl  a l c o h o l was not removed and the u s u a l r e a c t i o n procedure was followed. for  The t o t a l volume o f s o l v e n t  used was the same (40 ml )  each r u n . When l i t h i u m t - b u t o x i d e was the base used, i t was formed  by  adding two equivalent's  20 ml  of t-butyl alcohol.  addition of octalone Lithium  (2.0 mmol ) o f n - b u t y l l i t h i u m t o T h i s was f o l l o w e d  by the dropwise  (95) i n 20 ml. o f t - b u t y l  alcohol.  d i i s o p r o p y l a m i d e was prepared i n THF from 2.0 mmol  of d i i s o p r o p y l a m i n e and 2 mmo3 A f t e r the r e q u i r e d  length  o f methyl l i t h i u m . o f time f o r the r e a c t i o n  t o be  complete, the r e a c t i o n mixtures were quenched by p o u r i n g them i n t o 0.1 N h y d r o c h l o r i c *  a c i d and the r e s u l t a n t mixture was  extracted  The e t h e r e x t r a c t s were combined and  with ether.  washed w i t h water and b r i n e u n t i l n e u t r a l , d r i e d  (MgSO^), and  evaporated t o y i e l d a crude o i l . An e t h e r s o l u t i o n o f t h i s crude o i l was then i n j e c t e d i n t o a gas chromatograph t o determine the product At  ratios.  t h i s time, one e q u i v a l e n t  (1.0 mmol ) o f a "standard  compound", was added t o the crude r e a c t i o n mixture and a s o l u t i o n of the r e s u l t i n g mixture was i n j e c t e d i n t o a gas chroma*When HMPA was s o l v e n t , a Pet. was employed f o r e x t r a c t i o n .  Ether-Ether  (3:1)  mixture  -66-  tograph  t o determine  mixture  was  The  then  isolated  t h e G.L.C. y i e l d . *  distilled  yield  was  weight of the standard to  under reduced determined  compound  from  give the a c t u a l weight o f product All  in  then  Table  listed  The e n t i r e pressure  analysis  and w e i g h e d .  by s u b t r a c t i n g t h e  the t o t a l  distilled  weight  formed.  t h e r e a c t i o n s were r u n i n d u p l i c a t e a n d t h e numbers I I r e p r e s e n t an a v e r a g e  values  experimental  *For a f u l l  showed  a variation  value  f o r the r a t i o s .  o f ± % % from  values.  account  see s e c t i o n  II p a r t ( A ) .  The  the i n d i v i d u a l  (B)  INTRAMOLECULAR 1.  General  Under dynamically in the  t-butyl  t h e normal c o n d i t i o n s f o r g e n e r a t i n g the thermo-  favoured enolate alcohol,  a or y position  statement  ALKYLATION OF MESYLATE (95)  (101) u s i n g p o t a s s i u m  one w o u l d e x p e c t and n o t a t t h e  i s true provided that  formed d i e n o l a t e a n i o n  cyclization apposition.  alkylation  (102) i s much s l o w e r  t-butoxide  to occur at The a b o v e  o f the i n i t i a l l y than p r o t o n  transfer  ( r a t e _ i ^ rate3) .  (103)  (104)  J  (66)  -68-  Examples of systems c o n t a i n i n g an angular chain which have been s u b j e c t e d  to intramolecular  c o n d i t i o n s can be found i n the l i t e r a t u r e . l i s t e d below. these examples. was employed.  (65)  Some i n t e r e s t i n g Firstly,  one carbon  observations  alkylation  A few examples are can be made from  i n a l l cases c i t e d a p r o t i c  Secondly, the base used was a metal  (66)  solvent  alkoxide.  T h i r d l y , the p o s i t i o n o f a l k y l a t i o n was, i n a l l cases, gamma to  the c a r b o n y l group.  These r e s u l t s are i n accord w i t h  Scheme IV where proton t r a n s f e r o f the i n i t i a l l y anion i s much f a s t e r than a l k y l a t i o n .  formed e n o l a t e  However, the f a c t o r s  r e s p o n s i b l e f o r e x c l u s i v e gamma a l k y l a t i o n are as y e t n o t clear. Before undertaking t h i s study i t was f e l t p r e v i o u s l y d e s c r i b e d study  t h a t , as i n the  (section I I ) , c e r t a i n  parameters  would be p o t e n t i a l l y i n f l u e n t i a l i n determining the p o s i t i o n of  alkylation.  agent.  These f a c t o r s were, s o l v e n t , base and complexin  On the o t h e r hand i t was f e l t  t h a t f a c t o r s such as  t e m p e r a t u r e , r e a c t i o n c o n c e n t r a t i o n and c a t i o n would have or  minimal  i n f l u e n c e on the product r a t i o .  little  The r e s u l t s i n  Table I I c l e a r l y i n d i c a t e that the above p r e l i m i n a r y expectat i o n s , a t l e a s t i n p a r t , were i n f a c t  fulfilled.  E f f e c t of Solvent  2.  The  octalone  (95)  was s u b j e c t e d t o r e a c t i o n c o n d i -  t i o n s where the thermodynamic e n o l a t e anion Thus treatment o f keto mesylate in  (95)  (101)  was generated  with potassium  t - b u t y l a l c o h o l a t room temperature  t-butoxide  f o r twenty hours r e -  s u l t e d i n the formation o f a s i n g l e product i n 74% i s o l a t e d y i e l d as a c o l o u r l e s s o i l . formed v i a y - a l k y l a t i o n in  The product proved t o be the one  (see e x p e r i m e n t a l ) .  This result i s  a c c o r d w i t h Scheme IV where a l k y l a t i o n o f the i n i t i a l l y  formed d i e n o l a t e anion (rate_]^rate ). 3  (102)  i s slower than proton  transfer  -70OMs  -0  OMs  O  P  (95)  (103) Changing as  t-butyl  decrease  the r e a c t i o n  alcohol,  the rate  alkylation  medium f r o m a p r o t i c s o l v e n t ,  t o an a p r o t i c  solvent,  shift  anion  of the i n i t i a l l y  formed d i e n o l a t e  source  i s a p r o t i c solvent,  one  would expect  and  a minimal e q u i l i b r i u m  in  THF s h o u l d  formed  of potassium afforded,  the  i n order  i s necessary.  (102).  f o r the e q u i l i b r i u m  shift  show an i n c r e a s e  i n THF.  Thus,  product of Y-alkylation  alcohol  product  alcohol.  (95) (1.0 mmol  workup, a s i n g l e  o i l i n 61% i s o l a t e d y i e l d .  solvent,  the r e a c t i o n  ) with  i n THF a t room t e m p e r a t u r e  a f t e r the usual  dienolate  t-butyl  i n t-butyl  i n t h e amount o f  to t-butyl  of keto mesylate t-butoxide  Since  w h i l e THF i s an a p r o t i c  an e q u i l i b r a t i o n t o o c c u r  i n THF compared  Treatment  less  anion  i n f a v o u r o f t h e t h e r m o d y n a m i c a l l y more s t a b l e  (101), a p r o t o n  alcohol  s u c h a s THF, s h o u l d  o f e q u i l i b r a t i o n r e l a t i v e t o the rate o f  From Scheme I V i t i s c l e a r t h a t to  such  This  (2.0 mmol )  f o r 20 h o u r s  compound a s a  product proved  (see e x p e r i m e n t a l ) .  colour-  t o be  -71-  The  third  s o l v e n t s t u d i e d was HMPA.  HMPA  i s a dipolar  a p r o t i c s o l v e n t which i s known t o s o l v a t e c a t i o n s such as potassium We f e l t  and thus renders the e n o l a t e anion more r e a c t i v e .  t h a t a r e a c t i v e e n o l a t e anion would c y c l i z e a t a p o s i -  t i o n o t h e r than the gamma p o s i t i o n . mesylate  (95)  Thus treatment  o f keto  (1.0 mmol- ) w i t h 2.0 mmol.. o f potassium t —  butoxide i n HMPA a t room temperature  f o r 1 hour a f f o r d e d a  product mixture which showed two components by G.L.C. i n a r a t i o o f 20/80 f o r compounds  ( y/a").  C o i n j e c t i o n o f t h i s mix-  t u r e w i t h a u t h e n t i c gamma a l k y l a t e d product showed t h a t the minor component had t h e same r e t e n t i o n time as the gamma a l k y l a t e d product.  The i n f r a r e d spectrum  o f the mixture showed  a l a r g e a b s o r p t i o n , 1730 cm ^, which c o u l d be r e a d i l y buted t o a s a t u r a t e d c a r b o n y l .  This result strongly  attriindicated  t h a t the major product was the product of a - a l k y l a t i o n . A comparison  o f t h e r e s u l t s thus f a r d i s c u s s e d , (and i n  the e n t i r e study o f keto mesylate  (95)), c l e a r l y  indicated  • r e p r e s e n t i n g the product r a t i o asfy/a) i n d i c a t e s t h e f o l l o w i n g  The mole r a t i o o f  compound  (66) t o  (66)  compound  (104)  i s r e p r e s e n t e d by ( Y / C )  C104)  -72-  t h a t d i f f e r e n t r e s u l t s were o b t a i n e d as the s o l v e n t .  when HMPA was employed  I t would appear l o g i c a l a t t h i s time t o  examine and compare the p o s s i b l e t r a n s i t i o n s t a t e s o f the r e a c t i o n i n the three  solvents  In a p r o t i c s o l v e n t expect the e n o l a t e  such as t - b u t y l a l c o h o l , one would  anion t o be h e a v i l y s o l v a t e d .  would render the e n o l a t e s o l v a t e d enolate  studied.  This  condition,  anion l e s s r e a c t i v e r e l a t i v e t o a l e s s  anion such as one formed i n THF o r HMPA.  From t h i s i t c o u l d be argued t h a t the geometry o f t h e t r a n s i t i o n s t a t e f o r a l k y l a t i o n would be more p r o d u c t - l i k e than  reactant-  l i k e and the r e l a t i v e s t a b i l i t y o f the a - a l k y l a t e d product or the  y - a l k y l a t e d product would be r e f l e c t e d i n t h e r e l a t i v e  energy o f the two p o s s i b l e t r a n s i t i o n s t a t e s That i s t o say,  (see Scheme V ) .  i n t - b u t y l a l c o h o l and i n THF the t r a n s i t i o n  s t a t e f o r y - a l k y l a t i o n i s o f lower energy l e a d i n g t o the more s t a b l e af 3-unsaturated ketone  (66)  and n o t to the l e s s s t a b l e  (66)  3^y-unsaturated ketone  (104)  (104).  However, i n HMPA, a s o l v e n t known f o r i t s a b i l i t y  to solvate  34 cations  , one would expect t h e e n o l a t e  anion t o be r e l a t i v e l y  SCHEME V  -74-  " f r e e " and t h e r e f o r e t-butyl alcohol.  r e l a t i v e l y more r e a c t i v e than i n THF or  From t h i s i t could be argued t h a t the t r a n s i -  t i o n s t a t e geometry l e a d i n g t o i n t r a m o l e c u l a r be more r e a c t a n t - l i k e and t h e r e f o r e  a l k y l a t i o n should  the r e l a t i v e s t a b i l i t y of  the p r o d u c t ( s ) should have minimal i n f l u e n c e on the course o f the  reaction. 3. To  E f f e c t o f Base a s c e r t a i n t h e e f f e c t o f base, on the p o s i t i o n o f  intramolecular sidered  (95), we a l s o con-  a l k y l a t i o n o f keto mesylate  l i t h i u m t - b u t o x i d e and l i t h i u m d i i s o p r o p y l a m i d e .  l i t h i u m t - b u t o x i d e was employed as base i n t - b u t y l  When  alcohol  there was no s i g n o f any product f o r m a t i o n a t room temperature. However, when the l a t t e r s o l u t i o n was r e f l u x e d f o r 24 hours, the p r o d u c t o f y - l k y l a t i o n was i s o l a t e d e x c l u s i v e l y .  When com-  a  paring  t h i s r e s u l t t o the r e s u l t o b t a i n e d w i t h potassium t —  b u t o x i d e i n t - b u t y l a l c o h o l i t becomes c l e a r t h a t the l i t h i u m dienolate  anion  (101) i s much l e s s r e a c t i v e than the potassium  dienolate  anion  (101).  As mentioned i n the p r e v i o u s study t h i s  r e a c t i v i t y d i f f e r e n c e between the potassium e n o l a t e the  l i t h i u m enolate  As p r e v i o u s l y  and  (101) i s probably a r e f l e c t i o n o f the r e s -  p e c t i v e metal-oxygen bond c h a r a c t e r . i s more c o v a l e n t  (101)  The l i t h i u m - o x y g e n bond  than the potassium-oxygen bond. demonstrated, i t i s p o s s i b l e  the k i n e t i c d i e n o l a t e  anion  (102) under c o n d i t i o n s where i t s  i n t e g r i t y i s maintained by employing l i t h i u m as base i n an a p r o t i c s o l v e n t such as THF. t i o n s i t should be p o s s i b l e  t o generate  t o form some  diisopropylamide Under these  a-slkylated  condi-  product.  TABLE I I - INTRAMOLECULAR  (95)  ALKYLATION5 OF KETO MESYLATE 0  OS-CH  (95) X  ENTRY  0M5  1  K^Bu  OMs  2  K^Bu  OMs  3  OMS  4  OMs  5  LDA  OMs  6  K OBu  OMs  7  K OBu  •All  entries  BASE •  ADDED REAGENT  SOLVENT  REACTION CONDITIONS  GLC  YIELD ISOLATED  PRODUCT RATIO  t-BuOH  20 h r s .  R.T.  77  74  0  100  t-BuOH  45 m i n .  R.T.  72.6  71  0  100  K^Bu  THF  20 h r s .  R.T.  63  60.5  0  100  Li OBu  t-BuOH  20 h r s . r e f l u x  79  74  0  100  2 days r e f l u x  96  92  0  100  HMPA  1 hr.  R.T.  74. 3  73  80  20  HMPA  30 m i n .  R.T.  77.7  75  92  8  18-Crown-6  fc  THF  fc  fc  18-Crown-6  done i n d u p l i c a t e .  2 e q u i v a l e n t s o f base  used i n a l l cases. I U l  I  -76-  1102).  Treatment of  (103)  of o c t a l o n e  (95)  (1.0 mmol ) w i t h  l i t h i u m d i i s o p r o p y l a m i d e i n THF  f o r 2 4 hours  t u r e a f f o r d e d o n l y the s t a r t i n g m a t e r i a l . above s o l u t i o n was a l k y l a t i o n was The  above e x p e r i m e n t a l r e s u l t s , were, to say the That the i n i t i a l  least,  e x p e c t a t i o n s were not  ful-  can only l e a d t o the c o n c l u s i o n t h a t a l k y l a t i o n of the  An examination  (104)  However, when the  r e f l u x e d f o r 2 days, the product of gamma  k i n e t i c d i e n o l a t e anion  (102),  at room tempera-  formed e x c l u s i v e l y .  very unexpected. filled  (2.0 mmol )  (101) and  (102)  i s a very unfavourable p r o c e s s .  of models of the two p o s s i b l e d i e n o l a t e anions  l e a d i n g t o the three p o s s i b l e products  (103),  (66), does not p r o v i d e any i n f o r m a t i o n as to the  reason f o r not o b s e r v i n g any  a " - a l k y l a t e d product.  From an  examination  of the models, a l l three products seem l i k e l y  be formed.  T h e r e f o r e , f o r reason(s) unknown t o us, the k i n e t i c  d i e n o l a t e anion  to  (102), a t l e a s t i n our hands under the r e a c t i o n  -77-  c o n d i t i o n s employed, d i d not a l k y l a t e , j u s t 4. The  equilibrated.  E f f e c t o f Complexing Agent observed  e f f e c t o f adding  (2.0 mmol ) o f 18-crown—  6 t o the r e a c t i o n medium was t h a t i t g r e a t l y enhanced the r e a c t i o n r a t e , d e c r e a s i n g the r e a c t i o n time necessary  f o r the d i s -  appearance o f s t a r t i n g m a t e r i a l from 20 hours t o 45 minutes. When 18-crown-6 was added t o a t - b u t y l a l c o h o l s o l u t i o n t a i n i n g potassium  t-butoxide  and o c t a l o n e  con-  (95) the product  ratio  d i d not change, o n l y the r e a c t i o n , time was g r e a t l y reduced. T h i s r a t e enhancement i s not s u r p r i s i n g s i n c e 18-crown-6 comp l e x e s with potassium  i o n and renders  the d i e n o l a t e anion un-  36 complexed and thus more r e a c t i v e . When HMPA was employed as s o l v e n t i n t h i s study of  y a l k y l a t e d product  gamma and 80% a l p h a .  formed decreased  the amount  from 100% gamma t o 20%  The e x p l a n a t i o n p r e s e n t e d  above c o u l d now  be t e s t e d . I f the above " t r a n s i t i o n - s t a t e " e x p l a n a t i o n i s v a l i d , i t s h o u l d be p o s s i b l e t o f u r t h e r i n c r e a s e the amount of a — a l k y l a t e d p r o d u c t by employing c o n d i t i o n s which render (101)  more " f r e e " i n HMPA.  the e n o l a t e  anion  By u s i n g a complexing agent, such  as 18-crown-6, i n c o n j u n c t i o n with HMPA, one would expect the e n o l a t e anion t o be very r e a c t i v e and t h e amount o f a - a l k y l a t e d product  t o i n c r e a s e r e l a t i v e t o c o n d i t i o n s were 18-orown-6 was not  present. Thus treatment potassium  of octalone  t-butoxide  (95) with  2 equivalents of  and 2 e q u i v a l e n t s o f 18-crown-6 i n HMPA  f o r 30 minutes a t room temperature a f f o r d e d a product  mixture  -78-  which showed two components by G.L.C. i n a r a t i o o f 92/8 (entry 7) .  C o i n j e c t i o n o f t h i s mixture w i t h a u t h e n t i c  gamma a l k y l a t e d  product showed t h a t the minor component had the same r e t e n t i o n time as the gamma a l k y l a t e d product. 5.  Synthetic  Application  I t has been p o s s i b l e  t o form the product o f gamma  a l k y l a t i o n e x c l u s i v e l y by using  bases such as l i t h i u m t-butoxide  or potassium t - b u t o x i d e i n s o l v e n t s  such as THF o r t - b u t y l  h o l w i t h o r w i t h o u t the presence of 18-crown-6.  alco-  The p r o d u c t  of a - a l k y l a t i o n has been r e a l i z e d as the major product when HMPA was employed as the s o l v e n t .  When 2 e q u i v a l e n t s o f  18-crown-6 was p r e s e n t i n a HMPA s o l u t i o n c o n t a i n i n g l e n t s o f potassium t - b u t o x i d e , was  2 equiva-  (1.0 mmol ) o f o c t a l o n e (95)  converted almost e x c l u s i v e l y i n t o the product o f a - a l k y l a t i o n .  Most Conditions  /  (95)  2 eq. 18-Crown-6 .2 eq. K^-OBu \-HMPA R.T.  92% (104)  These r e s u l t s a r e s y n t h e t i c a l l y very u s e f u l s i n c e i t i s  -79now  possible  sively of  t o form t h e p r o d u c t  under a v a r i e t y  a-alkylation,  reaction tion  o f gamma a l k y l a t i o n  of reaction  conditions  almost e x c l u s i v e l y ,  conditions.  A t no t i m e was  exclu-  and t h e p r o d u c t  under a c e r t a i n  set of  the product o f  a^-alkyla-  detected.  (C)  Structural  Assignment o f A l k y l a t i o n  Products  (103) When k e t o m e s y l a t e of  intramolecular  tained,  (95)  was  subjected  alkylation conditions  i n most c a s e s , was  the only  an a, B - u n s a t u r a t e d  to a  variety  p r o d u c t ob-  ketone.  The  N.M.R. s p e c t r u m o f t h i s k e t o n e showed a s i n g l e t 6=5.75 w h i c h could  be r e a d i l y  carbonyl.  attributed  The i n f r a r e d  to a v i n y l proton  spectrum e x h i b i t e d  adjacent to a  an a b s o r p t i o n a t  -80-  1675 On  cm  ^ which i s c h a r a c t e r i s t i c  the b a s i s  o f t h e above d a t a compound  as a p o s s i b l e p r o d u c t experiments  listed  structure  was  t o a l l o w one  To  s t u d y was  atoms w o u l d be  otherhand,  out  was  ruled  o b t a i n e d i n the f i r s t  determine  five  which  (103)  or  s t u d y was  (66)  a g-unsaturated ;  subjected to deuteration.  incorporated into  i f (66) was  sufficient  study, the . a,B-unsaturated  actual product obtained i n t h i s ium  (104)  t o d i s t i n g u i s h between  obtained i n this  formed i n t h i s  ketone,  data d i d not p r o v i d e  as t h e p r o d u c t s t r u c t u r e . ketone  c^B-unsaturated  i n Table I I .  However, t h e s p e c t r a l information  o f an  ketone  I f the  (103), t h r e e d e u t e r -  the molecule.  t h e p r o d u c t , o n l y two  On  deuterium  the atoms  w o u l d be i n t r o d u c e d .  D deuterated  To  this  end,  ethane-deuterium of  potassium  stir  (66)  deuterated  t h e p r o d u c t was  dissolved  o x i d e , i n the presence  h y d r o x i d e and  a t room t e m p e r a t u r e  the r e s u l t i n g  f o r 3 days.  f o l l o w e d by mass s p e c t r a l a n a l y s i s , atoms had  D  D (103)  i n 1,2-dimethoxy-  of a c a t a l y t i c s o l u t i o n was  left  I s o l a t i o n of the showed o n l y two  been i n t r o d u c e d i n t o the m o l e c u l e .  This  amount to  product,  deuterium latter  -81-  r e s u l t s t r o n g l y i n d i c a t e d t h a t compound  (66)*, the product  of gamma a l k y l a t i o n , was the ^ ^ - u n s a t u r a t e d ketone t h i s study and not compound  (103) the product o f  •Compound (66), i s a known compound  formed i n  a-alkylation.  (see r e f e r e n c e 39).  -82-  EXPERIMENTAL  GENERAL — • — '  t  •—  M e l t i n g p o i n t s , which were determined  on a F i s h e r - J o h n s  m e l t i n g p o i n t apparatus, and b o i l i n g p o i n t s are u n c o r r e c t e d . U l t r a v i o l e t s p e c t r a were measured i n methyl  alcohol  solution  u s i n g a Cary, model 14, spectrophotometer.  Routine  infrared  s p e c t r a were recorded on a Perkin-Elmer I n f r a c o r d model 710 spectrophotometer.  Proton magnetic  resonance  (^"H N.M.R.) spec-  t r a were, u n l e s s otherwise noted, r e c o r d e d i n d e u t e r o c h l o r o form s o l u t i o n on V a r i a n A s s o c i a t e s spectrometer A-60, T-60 and/or HA-100, XL-100.  L i n e p o s i t i o n s are g i v e n i n 6 u n i t s  w i t h t e t r a m e t h y l s i l a n e as an i n t e r n a l s t a n d a r d ; the m u l t i p l i city,  i n t e g r a t e d peak areas and p r o t o n assignments  cated i n parenthesis.  High r e s o l u t i o n mass s p e c t r a were r e -  corded on an AEI; type MS9, mass spectrometer. was performed  on a Hewlett Packard model 5830A  chromatography u n i t .  are i n d i -  G.L.C. a n a l y s i s gas-liquid  M i c r o a n a l y s e s were performed  by Mr. P.  Borda, M i c r o a n a l y t i c a l L a b o r a t o r y , U n i v e r s i t y of B r i t i s h Columbia,  Vancouver.  -83-  PREPARATION OF 2-ALLYLCYCLOHEXANONE  (80)  (80) A solution pyrrolidine  of cyclohexanone  (98 g, 1 mole) and  (.127.5 g", 1.5 mole") was r e f l u x e d  7 hours under  a Dean-Stark  water  separator.  i n benzene f o r The b e n z e n e  e x c e s s p y r r o l i d i n e were removed by d i s t i l l a t i o n crude p y r r o l i d i n e pure p y r r o l i d i n e b.p. 108-110°C  the  enamine i n 90% y i e l d  a solution  cyclohexanone  wise  of the l a t t e r  as a c o l o u r l e s s  o f 125 g o f t h e p y r r o l i d i n e  i n one l i t e r  120 g o f a l l y l solution  Distillation  to y i e l d the  bromide.  was r e f l u x e d  After  overnight  the a d d i t i o n (18 h o u r s )  was  under  r e m o v a l o f most o f t h e a c e t o n i t r i l e , by r o t a r y  tion,  t h e r e s i d u e was d i l u t e d w i t h 600 ml o f w a t e r  a steam  cooled  b a t h f o r 30 m i n u t e s .  and e x t r a c t e d w i t h e t h e r .  were d r i e d ,  o i l .  enamine  o f a c e t o n i t r i l e was added  After  on  afforded  (bath temperature) a t 13 mm.  To of  enamine.  and  The r e s u l t i n g The combined  c o n c e n t r a t e d and d i s t i l l e d  under  drop-  complete nitrogen. evapora-  and h e a t e d  solution ether  was  extracts  reduced pressure  t o y i e l d ketone (80) (92 g, 66% ) as a colourless l i q u i d ; b.p. 100-105°C (bath temperature) a t 19mm.  -84-  PREPARATION OF OCTALONE (82)  O (82) A s o l u t i o n o f 3.0 m l o f 3N NaOMe i n ( lOOg, 0.72 mmol) o f 2allylcyclohexanone  maintained  a t - 1 0 ° C was e f f i c i e n t l y  stirred  u n d e r an a t m o s p h e r e o f n i t r o g e n a n d ( 54g, 0.77 mmol) o f methyl v i n y l ketone was  added o v e r a p e r i o d o f 2 h o u r s .  hours a t -10°C, t h e r e s u l t i n g transferred thoroughly  using  ether  m  of  a hydroxyl  ether.  brine, dried  _ i80 g o f crude o i l .  t h i c k creamy r e a c t i o n m i x t u r e was  and w a t e r t o a s e p a r a t o r y  extracted with  were washed w i t h  T h e combined e t h e r  extracts  4  The i n f r a r e d  carbonyl  f u n n e l and  (MgS0 ) a n d e v a p o r a t e d t o g i v e  group, a s a t u r a t e d  an 0,6 - u n s a t u r a t e d  A f t e r an a d d i t i o n a l 24  s p e c t r u m showed t h e p r e s e n c e carbonyl  absorption.  absorption  as w e l l as  The e n t i r e crude mix-  t u r e was t h e n r e f l u x e d f o r 2 h o u r s i n a 5% s o d i u m m e t h o x i d e methanol s o l u t i o n , cooled acid. residue  and n e u t r a l i z e d w i t h  glacial  acetic  T h e " r e s u l t i n g n e u t r a l s o l u t i o n was e v a p o r a t e d a n d t h e extracted with  washed w i t h  ether.  brine, dried  The combined e t h e r e x t r a c t s were  (MgSO^), a n d e v a p o r a t e d t o g i v e  a crude  yellow o i l . D i s t i l l a t i o n under reduced pressure afforded ( 50g,72%) o f s t a r t i n g m a t e r i a l ; b.p. 100-105°C (bath temperature) a t 19mm, and (46g, 0.242mole) o f octalone (82); b.p. 110-115°C (bath temperature) a t 0.4 mm.  -85-  PREPARATION OF  ETHYLENE KETAL  A s o l u t i o n o f ( 5 g, 26.3 (4.6 ml /75.0  (83)  mmol ) o f o c t a l o n e  mmol ) of e t h y l e n e g l y c o l and  s u l f o n i c a c i d i n 160  ml o f benzene was  under a Dean-Stark water s e p a r a t o r . c o o l e d and  s o l i d NaHCO^ vas  sulfonic acid.  The  crude  e n t i r e s o l u t i o n was  ketal  (83).  -afforded pure ketal (83)  f o r 18  dried  hours  benzene s o l u t i o n  added t o n e u t r a l i z e the  tory, f u n n e l , washed w i t h H^O, yield  .1 g o f p - t o l u e n e -  refluxed  The  (82),  transferred  (MgSO^), and  p-toluenet o a separa-  evaporated  (5.5g, 92%) as a colourless o i l ; b.p. 135-145°C 1  1090 cm ; -1  p.m.r. 6=5.3 (m,4H,  vinyl) , 6=3.9 ( s, 4H, ketal H) . Mol. Wt. Calcd. for C H 0 : 234.161790. 22  2  Found (high resolution mass  spectrometry) 234.161971 . PREPARATION OF  to  D i s t i l l a t i o n under reduced p r e s s u r e  (bath temperature). at 0.5mm; i.r.' (film) X  15  was  KETAL ALCOHOL  r  (84)  OH  <84) To a s t i r r e d  s o l u t i o n of { 14.3 ml ,'0.131 mole)  2-methyl-2-butene i n 100 ml of THF of N  2  , was  complex. 26.3 was  added (6.72ml, After  i n 4 0 ml THF was  t o stir  mixture was  atmosphere  0.065 mole) of a d i m e t h y l s u l f i d e - b o r a n e  1 hour a t 0° C a solution of octalone (83)  mmol. ) left  at 0° and under an  (5.0 g,  added and the r e a c t i o n mixture  2 hours at room temperature.  The  reaction  once a g a i n c o o l e d to 0 ° c and 85 ml of 3N NaOH solution was  added dropwise w i t h c a r e , f o l l o w e d by c a r e f u l dropwise a d d i t i o n of  85 ml of 30% 2 ° 2 * H  T  *  temperature and s t i r r e d s u l t i n g o i l was combined  l e  r e a c t  ^-  mixture ^ s warmed to room  o n  w  f o r 3 hours then c o n c e n t r a t e d .  d i l u t e d with H 0 2  and e x t r a c t e d with e t h e r .  e t h e r e x t r a c t s were washed w i t h b r i n e , d r i e d  and e v a p o r a t e d to g i v e 5.5 g o f crude k e t a l a l c o h o l 78% p u r i t y by G.L.C.  The r e -  Chromatography  (MgSO^),  (84) i n  on s i l i c a g e l and  w i t h a petroleum e t h e r - e t h e r mixture a f f o r d e d  The  eluting  (4.6 g , 70% ) of pure  ketal alcohol (84) as a colourless o i l . An .'analytical sample 'was obtained  try preparative gas liquid chromatography. i . r . (film)  *  m  a  x  3450 cm ^ ( h y d r o x y l ) ;  p.m.r. 6=5.4  (nijlH,  v i n y l ) , 6=4.0 (s , 4H, k e t a l H) , 6=3.6 (m, 2H, CH 0H) . 2  Mol.Wt. c a l c d .  for T_5 24°3 c  H  :  252.1726.  mass spectrometry) ,(252.1726). PREPARATION OF KETAL MESYLATE  ( 8 5 )  (85)  Found  (high  resolution  -87-  To  an i c e c o l d  solution  of ketal  mmol ) a n d methane s u l f o n y l c h l o r i d e methylene (17.7  chloride  mmol  ).  p h e r e was l e f t The  cold mixture  alcohol  (84) (3 g, 11.8  (1.5 g,13 mmol- ) i n 80 m l o f  was added d r o p w i s e  1.8 g o f  triethylamine  The r e s u l t i n g m i x t u r e u n d e r a n i t r o g e n to s t i r  f o r 45 m i n u t e s t h e n p o u r e d i n t o  atmosice  water.  was extracted using methylene chloride, d r i e d (MgSO^) and eva-  porated under reduced pressur t o y i e l d the crude k e t a l mesylate , (100) in  100% y i e l d : p.m.r.  i . r , (film)  x  1450,1350,1170,109 0 c m  m a v  6=5.5 (m, IH, v i n y l ) , 6-4 . 3  (unresolved  - 1  ;  (m, 2H , -CH -0 Ms) , 6=3.8 2  d o u b l e t ) 4 H , k e t a l H) and 6=3.0  (s,3H,0-S-CH3>.  PREPARATION OF KETAL CHLORIDE (86)  I  Cl  -(86) A s o l u t i o n o f k e t a l mesylate (85) (3.5 g, 11.8. mmol)  and  lithium  chloride  f o r 18 hours. and  ('2.5 g, 60 mmol ) was r e f l u x e d i n acetone  At t h i s time the r e a c t i o n  evaporated under reduced p r e s s u r e .  mixture was c o o l e d The r e s u l t i n g  residue I  was d i l u t e d w i t h H 0 and e x t r a c t e d w i t h e t h e r . 2  e t h e r e x t r a c t s were washed with b r i n e , d r i e d  (MgSO^) and evapor-  a t e d t o y i e l d crude k e t a l  chloride  94%  sample was prepared by column chrom-  yield.  An a n a l y t i c a l  atography on s i l i c a  gel,  eluting  leum e t h e r / e t h e r :  i . r . (film)  (86),  The combined  as an o i l (2.55 g)  in  with a 50/50 mixture o f p e t r o X  1450,1090 c m ; -1  a  v  -88-  p.m.r. 6=5.48  (m,1H,vinyl), 6=3.98 (s,4H,ketal H) , 6 = 3.5  (m,2H,-CH -C1) . 2  PREPARATION OF OCTALONE (77a) ,  Cl  (77a) To a s o l u t i o n of k e t a l c h l o r i d e  (86) (2.55 g, 9.0 mmol ) i n  20% aqueous acetone was added 0.3 ml o f c o n c e n t r a t e d s u l f u r i c a c i d and the r e a c t i o n r e f l u x e d f o r 14 hours.  The r e a c t i o n mix-  t u r e was then c o o l e d n e u t r a l i z e d w i t h NaHCO^ and acetone ated under reduced p r e s s u r e .  The r e s u l t i n g r e s i d u e was d i l u t e d  w i t h F^O and e x t r a c t e d w i t h e t h e r . were washed w i t h crude  dried  evapor-  The combined e t h e r e x t r a c t s  (MgSO^), and evaporated t o y i e l d  a 3-unsaturated keto c h l o r i d e  (77a).  Chromatography on  s i l i c a g e l , and e l u t i n g w i t h a petroleum e t h e r - e t h e r mixture gave (1.9 g, 90% from^-aijof octalone (77a); b.p. 125-135°C (bath temperature) at .03mm; i . • (film) r  \ "max 1660 (conj. carbonyl) and 1620 c m  unsaturation);  - 1  (conj.  p.m.r. 6=5.75 ( s , I H , v i n y l ) , 6 -3.5 (m,2H,  -CH -C1). 2  Mol.Wt. c a l c d . f o r C H C 1 0 : 1 3  t i o n mass spectrometry)  l g  226.112423.  226.111946.  Found  (high r e s o l u -  -89-  PREPARATION  OF  KETAL IODIDE  (87)  I  A solution of k e t a l mesylate sodium  iodide  (85) (3.6 mmol ) ,  (18.0 mmol ) and sodium  b i c a r b o n a t e (4.0 mmol )  i n acetone was r e f l u x e d f o r 20 hours.  A t t h i s time the r e a c -  t i o n was c o o l e d and evaporated under reduced p r e s s u r e .  The  r e s u l t i n g r e s i d u e was d i l u t e d with E^O and e x t r a c t e d w i t h e t h e r . The  combined e t h e r e x t r a c t s were washed w i t h E^O, b r i n e ,  sodium  t h i o s u l f a t e , U^O,  y i e l d crude k e t a l i o d i d e 1240, 1090 cm" ;  dried (87): '  p.m.r.  1  (MgSO^) and evaporated t o i. . r  (film)  A  1450, max  6=5.4 (m, IH, v i n y l ) , 6 -3. 9 (., s  4H,ketal H) , 6=3.2 (m, 2H,-CH -I) . 2  PREPARATION OF OCTALONE (77b) I  (77b) To a s o l u t i o n o f crude k e t a l i o d i d e 10% aqueous acetone  (40 ml) was added dropwise  (87) 0.860 g i n 0.15 ml o f con-  c e n t r a t e d s u l f u r i c a c i d and the r e a c t i o n mixture was r e f l u x e d f o r 18 hours.  The r e a c t i o n mixture was then c o o l e d , n e u t r a l i z e d  -90-  with s o l i d NaHCO^ and evaporated  under reduced  pressure.  The  r e s u l t i n g r e s i d u e was d i l u t e d with 1^0 and e x t r a c t e d w i t h The  ether.  combined e t h e r e x t r a c t s were washed with b r i n e , d r i e d (MgSO^)  and evaporated compound.  to y i e l d iodide  Recrystallization  (77b) as a white  from petroleum  crystalline  ether-ether afforded  the iodide (77b) (350 mg , 30% front the ketal alcohol) as white needles 1655 (conj. carbonyl), 1615 c m " 1 (ccnj.  m.p. 60-61°C; i . r . (film) X  unsaturation) ; p.cur-. 6= 5.7 (s. , 1H_, vinyl proton) , < S = 3.2 ( m , 2H ,  -<H 2 -U'. Mol.Wt. c a l c d . f o r  C  mass s p e c t r o m e t r y )  H 1  3  I 1  :  9  318.0484.  2.0 mmol  (prepared  #1  o f d i i s o p r o p y l a m i d e and  to s t i r  of octalone  (77a).  The s o l u t i o n  f o r 3 hours a t room temperature then quenched  i n t o 50 ml of 0.1 N HCl s o l u t i o n .  The r e s u l t i n g  was e x t r a c t e d with ether and e t h e r e x t r a c t s were washed  w i t h H^O, d r i e d (MgSO^) and evaporated (91).  ( e n t r y 2 T a b l e I)  of n - b u t y l l i t h i u m ) was added, dropwise, under a  by pouring mixture  (91)-  from 2.2 mmol  n i t r o g e n atmosphere, 1.0 mmol was l e f t  (high r e s o l u t i o n  318.0482.  PREPARATION OF OCTALONE  propylamide  Found  t o y i e l d crude o c t a l o n e  Hot box d i s t i l l a t i o n under reduced  pressure  afforded  -91-  pure o c t a l o n e b.p.  (91)  as a c o l o u r l e s s o i l i n 57%  115-125°C (bath temperature) at 0.2 ; ^  (conj. carbonyl), 1620 cm  mm;  yield;  i.r.X  1670  cm  - 1  max  (conj. unsaturation) ; p.m.r.<5= 6.02  ( s, IH, vinyl). Mol.Wt. c a l c d . f o r  c  i 3 i H  0  :  1 9 0  8  '  1 3 5 7  «  Found  (high  resolution  mass spectrometry) 190.1363. CYCLIZATION OF  KETO IODIDE (77b)  (entry  I)  9 Table  IN t-BUTYL ALCOHOL  (77b) To in  a s o l u t i o n of potassium t - b u t o x i d e  t - b u t y l a l c o h o l at room temperature and  of nitrogen, (1.0 for  (91)  was  15 minutes and  extracted  of a 0.1  quenched by N HCl  w i t h e t h e r and  washed w i t h H 0, 2  octalone  (91).  octalone  (91)  under an  mmol )  atmosphere  added dropwise a s o l u t i o n of o c t a l o n e  mmole) i n t - b u t y l a l c o h o l .  i n t o 50 ml  (2.0  dried  The  left  to  stir  pouring the r e a c t i o n mixture  solution. the  r e a c t i o n was  (77b)  The  r e s u l t i n g mixture  was  combined e t h e r e x t r a c t s were  (MgS04) and  evaporated to y i e l d  P u r i f i c a t i o n by d i s t i l l a t i o n a f f o r d e d as a c o l o u r l e s s o i l i n 94%  crude pure  isolated yield.  PREPARATION OF  OCTALONE (90)  (entry  1 Table  I)  (90) To in  a s o l u t i o n of potassium t-butoxide  t-butyl alcohol  of n i t r o g e n (1.0  was  a t room temperature and  The  at room temperature f o r 4 hours and r e a c t i o n mixture i n t o 50 ml r e s u l t i n g mixture was  88:12, by  r e a c t i o n was  N HCl  were washed w i t h ^ 0 ,  dried  i.r.  following (film)  The  two  The  stir  the  The  combined  (M^SO^) and  evapor-  crude o i l of  components were  column chromatography u s i n g s i l i c a  the  to  components i n a r a t i o  w i t h a petroleum e t h e r - e t h e r mixture.  the  the  D i s t i l l a t i o n of the  g a s - l i q u i d chromatography.  proved to be  (77a)  left  solution.  w i t h e t h e r and  a product which showed two  s e p a r a t e d by  atmosphere  quenched by p o u r i n g  of a 0.1  extracted  ated to y i e l d a crude o i l . afforded  under an  mmol )  added dropwise a s o l u t i o n of o c t a l o n e  mmol. ) i n t - b u t y l a l c o h o l .  ether extracts  (2.0  g e l and  eluting  major product  product of . a - a l k y l a t i o n , o c t a l o n e  (90),  from  data. A  m  a  x  1710  cm  -1  (sat. c a r b o n y l ) ;  p.m.r.  5=5.55  (t, IH, v i n y l , J = 2.0 Hz) . Mol.Wt. c a l c d .  for  C T ^ H ^ O :  mass spectrometry) 190.1352.  190.1357.  Found  (high  resolution  -93-  Experimental Procedure  (Entry 2 Table I)  E x p e r i m e n t a l procedure was as above w i t h the a d d i t i o n o f 2.0 mmol  of 18-crown-6 and r e a c t i o n time of  only 15 minutes. E n t r y 3 Table I E x p e r i m e n t a l c o n d i t i o n s were the same as f o r entry 1 Table I u s i n g THF as s o l v e n t and not t - b u t y l  alcohol.  Entry 4 Table I E x p e r i m e n t a l c o n d i t i o n s were as above w i t h the a d d i t i o n o f 2.0 mmol 15  o f 18-crown-6 and r e a c t i o n time o f o n l y  minutes. E n t r y 5 Table I E x p e r i m e n t a l c o n d i t i o n s were the same as f o r e n t r y 1  T a b l e I u s i n g HMPA as s o l v e n t i n s t e a d o f t - b u t y l  alcohol.  E n t r y 6 Table I A s o l u t i o n o f l i t h i u m t - b u t o x i d e was prepared by adding 2.0 mmol  o f methyl  atmosphere o f n i t r o g e n . wise  l i t h i u m t o t - b u t y l a l c o h o l under an  To the above s o l u t i o n was added drop-  1.0 mmol . o f o c t a l o n e  (77a) i n t - b u t y l a l c o h o l .  The  r e s u l t i n g mixture was r e f l u x e d f o r 6 hours and quenched i n the u s u a l manner.  Workup a f f o r d e d a mixture o f  a and a - a l k y l a t e d  products. Entry  8 Table I E x p e r i m e n t a l c o n d i t i o n s were s i m i l a r t o those em-  -94-  ployed f o r e n t r y 2 Table I , except f o r the f o l l o w i n g changes. Firstly  the s o l v e n t used was a 40:60 mixture o f t - b u t y l  THF c o n t a i n i n g 2.0 mmol  o f 18-crown-6.  alcohol:  The s t a r t i n g m a t e r i a l  was added a t -7 8°C and the reaction mixture was allowed to warmup to room temperature  over a p e r i o d of 30 minutes.  T h i s was f o l l o w e d  by an a d d i t i o n a l 15 minute p e r i o d of s t i r r i n g a t room  temperature  b e f o r e the r e a c t i o n was quenched. Entry 9 Table I E x p e r i m e n t a l c o n d i t i o n s were the same as those employed f o r e n t r y T a b l e I except t h a t the r e a c t i o n time was o n l y 15 minutes. E n t r y 10 T a b l e I E x p e r i m e n t a l c o n d i t i o n s were the same as those i n e n t r y 2 Table I . E n t r y 11 T a b l e I E x p e r i m e n t a l c o n d i t i o n s were the same as those used i n e n t r y 8 T a b l e I . PREPARATION OF OCTALONE (93)  ( 9 3 )  used  -95-  Compound (93) v a s prepared from o c t a l o n e (90) 37 u s i n g Barton's W o l f f - K i s h n e r Octalone of  c o n d i t i o n s es o u t l i n e d below.  (90) (2.47 mmol ) was allowed t o r e a c t w i t h 25 ml  a 1.45 K sodium g l y c o l a t e s o l u t i o n c o n t a i n i n g anhydrous  h y d r a z i n e a t 165°C-for 12 hours under protection fror, atmospheric moisture. tilling for  The r e a c t i o n temperature  was r a i s e d t o 210°C by dis-  e x c e s s h y d r a z i n e from t h e v e s s e l .  After refluxing  an a d d i t i o n a l 8 h o u r s , t h e c o o l e d s o l u t i o n was d i l u t e d  w i t h E^O and e x t r a c t e d w i t h petroleum  e t h e r 30-60°C. The o r g a n i c  e x t r a c t s were combined, washed w i t h I^O, d r i e d  (MgSO^) and  evaporated under a s p i r a t o r p r e s s u r e u s i n g no heat t o y i e l d a colourless o i l . D i s t i l l a t i o n under reduced pressure afforded (0.35g, 80.6%) of a colourless o i l ; b.p. 135-140°C (bath temperature) at 7.0mm; i . r . (film) X  1450 cm , 1090 cm" -1  1  (no carbonyl) ; p.m.r. 6=5.4 (t, IH, J=2.0 Hz, vinyl H)  PREPARATION OF OCTALONE  (9 2)  592)  Octalone (92)fcrasprepared from octalone $93) asing the Collins oxidation procedure as follows. Octalone (93) (.195 Q j l . l l maol ) was dissolved in dichloromethane and was added to a snagnetically stirred red solution containing a 15 fold excess of a 1:1 complex of pyridine and chromium trioxide in  -96-  dichloromethane.  The r e a c t i o n was  at which time i t was an alumina bed  filtered  A f t e r d i l u t i o n w i t h H^O,  the  drawn o f f and d i s c a r d e d and the o r g a n i c  was washed w i t h J^O, centrated.  f o r 6 hours  through c e l i t e and passed through  (Activity III).  aqueous phase was  l e f t to s t i r  3N HC1  solution, dried  The r e s u l t i n g r e s i d u e was  layer  (MgSO^) and con-  distilled  under reduced  pressure to afford (0.18 g, 85%)- of octalone (92) as a colourless o i l ; b.p.125135°C (bath temperature) at 0.2mm; i.r.  (film)  \  1660  unsaturation)',  cm ^ (conj. carbonyl) 1620  p.m.r. 6 = 5.76  (conj.  (sharp s IH, v i n y l ) .  Mol.Wt. c a l c d . f o r C H O=190.1357. 13  cm  lg  Found  (high  resolution  mass spectrometry) 190.1357. PREPARATION OF 2-CARBOMETHOXYCYCLOHEXANONE  (14 5)  COOCH  (145) To a s t i r r e d mixture of sodium h y d r i d e (30.7 g) dimethylcarbonate  (288 g) i n 500 ml o f dioxane was  under an atmosphere  added w h i l e  o f n i t r o g e n 63 g of cyclohexanone dropwise  over a p e r i o d o f 4 hours a t a c o n s t a n t temperature o f The s o l u t i o n was  left  80-85°C.  t o s t i r an a d d i t i o n a l 12 hours, c o o l e d and  a c i d i f i e d by the slow a d d i t i o n of 10% a c e t i c a c i d . was  and  The  removed under a s p i r a t o r p r e s s u r e , the r e s i d u e was  with H„0 and e x t r a c t e d w i t h e t h e r  (3x200 m l ) .  The  solvent  diluted  combined  -97-  e t h e r e x t r a c t s were washed with r ^ O , sodium b i c a r b o n a t e , b r i n e , dried  (MgSC> ) and c o n c e n t r a t e d to y i e l d 4  87 g o f crude p r o d u c t .  Vacuum, d i s t i l l a t i o n afforded pure 2-carbomethoxycyclohexanone (85 g, 85% ) as a colourless o i l ; b.p. 105- 107 C (bath temperature ) at 30nm; p.m.r. 6 =1.25 (s, IH :  O  enol H ), 6=3.5 (s, '3H, C-O-CH,).  PREPARATION OF OCTALONE (97)  COOCH  0  (97) To a s t i r r e d s o l u t i o n o f sodium methoxide (made from 2.76 g o f sodium i n added dropwise(15.6 g,  (120 mmol )  80 ml o f CH OH), a t -78°C was 3  100 mmol ) o f 2-carbomethoxycyclohexanone  over a p e r i o d o f 5 minutes.  A f t e r a f u r t h e r 2 minutes o f s t i r -  r i n g , (8.4 g , 120 mmol ) o f methyl v i n y l ketone was added dropwise.  The r e a c t i o n was allowed t o warm up t o room temperature  over a p e r i o d o f one hour then quenched by p o u r i n g i t i n t o some water.  The r e s u l t i n g mixture was e x t r a c t e d w i t h c a r b o n t e t r a -  c h l o r i d e and the combined e x t r a c t s washed w i t h H 2 O , d r i e d ( M g S O ^ and c o n c e n t r a t e d t o y i e l d Vaccuum d i s t i l l a t i o n  18.3 g of a crude orange o i l . 1  a f f o r d e d octalone (97) (18 g, 87%) as a colourless o i l  b.p. 160-164°C (bath temperature) at 0,7 jrm; i . r . (film) X  1710 cm  -1  ( ester  ITlcLX  carbanyi), 1680 cm  1  (conjugated carbonyl), 1640 cm  -1  (conj. unsaturation);  -98-  e  p.m.r .  =5.95 (s, IH, vinyl), <§=5.8 (s, 3H, C-CCH.,) .  PREPARATION  OF  KETAL  (9 8)  COOCH  3  (98) A  (8.0 g , 0.13  s o l u t i o n of  (13.6 g, 0.065 mole) Tceto e s t e r  mole) of e t h y l e n e g l y c o l and 0.200 g of p - t o l u e n e -  s u l f o n i c a c i d i n 150 ml of benzene was under a Dean-Stark water s e p a r a t o r .  r e f l u x e d f o r 24  The  r e a c t i o n mixture was  temperature) at  The benzene l a y e r was  to g i v e a crude o i l .  (9 8)  1080, 980,940 cm" ; 1  then d r i e d  (MgSO^)  Vacuum d i s t i l l a t i o n a f f o r d e d  i . r , ( f i l m ) . X__  v  p.m.r.  (s 4H,ketal H) , 6 = 3.7 A n a l . Calcd. f o r x 4 H 2 o ° 4 H,  entire  (80%) as a slightly yellow o i l ; b.p. 130-140°C  0.50 mm;  c  The  was  then t r a n s f e r r e d to a s e p a r a t o r y f u n n e l  and washed w i t h water. and evaporated  hours  r e a c t i o n mixture  then c o o l e d and t r e a t e d w i t h sodium b i c a r b o n a t e .  ketal ester  (97),  1720  ( e s t e r carbonyl)  6=5.65 (m,lH v i n y l H ) , .6=4.0  (s,3H, 0-OCH_ ) . 3  :  C  '  6 6  - ' 7  H  '  7  «9.  8.1.  PREPARATION OF KETAL ALCOHOL ,  (99)  -OH  (99)  (bath  Found C,  66.48;  -99-  To ketal ester of for  a THF s o l u t i o n  (98) at 0°C, under  L i A l H ^ . The r e a c t i o n 1 hour  NH.C1 4  was  and q u e n c h e d  solution.  After  i t was  (120 ml) c o n t a i n i n g  (22 g, .094 mole) of  , was added i n portions,  (3.3 g , 86.6 mmol)  left  to s t i r  by t h e s l o w sufficient  solution  was  e v a p o r a t e d and t h e r e s i d u e was  ether  l a y e r was  solid  oil.  ether-ether  afforded  i  r  (hydroxyl) ; H) , ,6=3. 25  through  added  celite.  The  filtrate  t a k e n up i n e t h e r - H 0 .  The  2  89-91°.C  alcohol  a semi-  x  i ^ r . (CHC1-.) ,3  6=5.1  petroleum  (99)) as a w h i t e  IT  p.m.r.  of a  to gelatinize  R e c r y s t a l l i z a t i o n from  pure k e t a l  m.p.  •  of petroleum ether-ether mixture  the a l c o h o l .  compound;  was  (MgSO^) and e v a p o r a t e d t o y i e l d  The a d d i t i o n  crystallized  talline  then f i l t e r e d  dried  (dropwise) a d d i t i o n  NH.C1 4  the  a t room t e m p e r a t u r e  (m,lH, v i n y l  A  3500  cryscm"  1  max  H) , 6 =3.6  (s,4H,ketal  ( s,2H,-CH -OH) . 2  PREPARATION  OF KETAL MESYLATE  (100)  (100) To  an i c e c o l d  solution of ketal  alcohol  (99) (2.24 g,  10 mmol' ) and m e t h a n e s u l f o n y l c h l o r i d e (12 mmol ) i n 70 m l of methylene nitrogen,  chloride  was  added  dropwise,  18.0 mmol' o f t r i e t h y l a m i n e . to s t i r  f o r 45 m i n u t e s  under  an a t m o s p h e r e  The r e s u l t i n g  was  left  then poured  into  The  cold mixture was extracted with methylene c h l o r i d e , and the  mixture  i c e water.  of  -100-  ccmbined extracts were dried (MgSO^) and evaporated to yield the crude ketal mesylate ( 3.0 g, 100% ) as an o i l y solid . Recrystallization from a petroleum e t h e r - e t h e r mixture c o n t a i n i n g 5% c h l o r o f o r m a f f o r d e d white needlesjm.p. 1170,1090,940 c m .  102-102.5°C- i . .  (CHC1 ) ' X  r  3  1350,  m a x  p.m.r. 6=5.6 (m,lH,vinyl H), 6 = 4 . 2  -1  (m,2H,-CH -OMs) , . 6=3. 0 ( s, 3H ,OS-CH ) 6=3.85 (s,4H,ketal H) . 2  3  Mol.Wt. c a l c d . f o r C H O S = 3 0 2 . 14  22  5  .  Found  (high r e s o l u t i o n  mass spectrometry) 302.1173. PREPARATION OF OCTALONE  (95)  (95) i  To a s o l u t i o n of k e t a l mesylate 10 mmol ) i n 10% aqueous acetone  (100)  (60 ml) was  ( 3.0 g,  added  dropwise  1 ml of c o n c e n t r a t e d s u l f u r i c a c i d and the r e a c t i o n mixture allowed to r e f l u x f o r 24 hours.  The r e a c t i o n mixture was  was  then  c o o l e d , n e u t r a l i z e d w i t h sodium b i c a r b o n a t e , and acetone  evapor-  ated under reduced p r e s s u r e .  ex-  tracted with ether. with brine, dried  The r e s u l t i n g r e s i d u e was  The combined e t h e r e x t r a c t s were washed  (MgSO^), and c o n c e n t r a t e d to y i e l d o c t a l o n e  (95) as a white c r y s t a l l i n e compound i n 68% i s o l a t e d  yield.  R e c r y s t a l l i z a t i o n from a mixture o f c a r b o n t e t r a c h l o r i d e - h e x a n e c o n t a i n i n g 5% EtOH a f f o r d e d white needles of  a,3-unsaturated  -101-  keto mesylate (conj.  (95) ; in. p. 98-99°C;  carbonyl),  980,940 c m  - 1  1620 cm""  1  ;  2  Mol.Wt. c a l c d .  (conj.  p.m.r. 6=5.8  - C H - 0 M S j , 6 =3.0  i . r . (CHCl-J j  X  1670 c m  - 1  max  u n s a t u r a t i o n ) , 1350,1170,  ( s , l H , v i n y l H ) , 6=4.33  (s,2H,  (s,3H,OS-CH ) . 3  for C  mass s p e c t r o m e t r y )  1 2  H  i g  0 S=258.  .  4  Found  (high  resolution  258.0918.  PREPARATION OF OCTALONE (66)  (66) To in  t-butyl  of  nitrogen,  a s o l u t i o n o f potassium t-butoxide  alcohol  into  was a d d e d d r o p w i s e a s o l u t i o n o f o c t a l o n e (95) in t-butyl  50 m l o f a 0.1 N HC1 s o l u t i o n .  The r e s i d u e  product (74%) A  The r e a c t i o n  1660 cm  was l e f t  the reaction  mixture  T h e r e s u l t i n g m i x t u r e was  w i t h e t h e r and t h e combined e t h e r e x t r a c t s  w a s h e d w i t h H^O, d r i e d oil.  alcohol.  f o r 20 h o u r s a n d q u e n c h e d by p o u r i n g  extracted  mole)  a t room t e m p e r a t u r e a n d u n d e r an a t m o s p h e r e  (0.258g, 1.0 mmol ) to s t i r  (2.0  were  (MgSO^) a n d e v a p o r a t e d t o y i e l d  a crude '  was d i s t i l l e d under reduced pressure t o a f f o r d a  which showed one component by gas liquid chromatography; i . r . (film) 1  (conj. carbonyl); p.m.r. 6= 5.75 (s, IH, vinyl).  Mass spectral peak 162.  -102-  PREPARATION OF OCTALONE  (10 4)  (104) To a s o l u t i o n in  o f potassium t-butoxide  30 ml o f HMPA c o n t a i n i n g  dropwise  1.1 mmol  reaction,  (2.0 mmol ) o f 18-crown-6 was added  of octalone  under an atmosphere  (95) i n 20 m l o f HMPA. o f n i t r o g e n , was l e f t  room t e m p e r a t u r e f o r 30 m i n u t e s . poured i n t o with  The combined  (7x50 ml) w i t h H,>0 , d r i e d crude o i l .  The r e a c t i o n  50 m l o f a 0.1 N H C l s o l u t i o n  pentane.  Distillation  by g a s - l i q u i d  chromatography.  185 MP  (£15);  component  A  (5x50 ml)  were washed  4  tive  i . r . (film)  m i x t u r e was t h e n  (MgS0 ) a n d c o n c e n t r a t e d  T h e two components  data, '  to s t i r at  and e x t r a c t e d  pentane e x t r a c t s  r a t i o o f 92:8.  The m a j o r  The  to yield a  ..under reduced pressure afforded'.a c l e a r o i l  w h i c h showed 2 components  gas-liquid  (2.0 mmol )  , max  chromatography  were s e p e r a t e d b y p r e p a r a -  (104) h a d t h e f o l l o w i n g  1720 cm  1  (sat. carbonyl); 1  p.m.r. 6=5.35  i na  ( t , l H , v i n y l H),6  1  spectral  U.V. ^ A max  3.55 ( t , l H ,  C-C-C=0) , 6 =2.5 ( m,2H,CH -C=0) . The m i n o r component p r o v e d t o be o c t a l o n e ' ( 6 6 ) . 2  Experimental Procedure  f o r Reaction Given i n Table I I  Entry 2 Table I I E x p e r i m e n t a l c o n d i t i o n s were as those used f o r entry 1 ( Table II  ) with the a d d i t i o n o f 2.0 mmol  of  18-crown-6 . Entry 3 Table I I E x p e r i m e n t a l c o n d i t i o n s were as those used f o r e n t r y 1  (  Table I I ) except t h a t THF was used as s o l v e n t i n s t e a d o f  t-butyl  alcohol.  Entry 4 Table I I E x p e r i m e n t a l c o n d i t i o n s i n v o l v e d adding 2.0 mmol of methyl  l i t h i u m t o t - b u t y l a l c o h o l f o l l o w e d by the dropwise  a d d i t i o n o f 1.0 mmol was  of octalone  (95).  The r e s u l t i n g  solution  then r e f l u x e d f o r 20 hours and worked up i n the u s u a l manner. Entry 5 Table I I To a room temperature  propylamide 2.0 mmol  s o l u t i o n of l i t h i u m  diiso-  (prepared from 2.2 mmol- o f d i i s o p r o p y l a m i d e and  o f n - b u t y l l i t h i u m ) was added dropwise,  mosphere o f n i t r o g e n , 1.0 mmol s o l u t i o n was s t i r r e d  of octalone  (95).  under an a t The r e s u l t i n g  f o r 2 days a t r e f l u x temperature  then  quenched and worked up i n the u s u a l manner. Entry 6 Table I I E x p e r i m e n t a l procedure was the same as t h a t  used  f o r e n t r y 1 Table I I except HMPA was employed as s o l v e n t i n s t e a d o f t - b u t y l a l c o h o l and the r e a c t i o n time was o n l y 30 minutes.  -104-  DEUTERATION  OF  OCTALONE  (66)  deuterated Deuterium oxide was octalone was  (66)  added t o a s o l u t i o n of  (66) i n 1 ml of 1,2-dimethoxyethane u n t i l  s a t u r a t e d ( .5 ml D^O).  hydroxide was  added and  a t u r e f o r 3 days.  A c a t a l y t i c amount of  the mixture was  The mixture was  a c i d and e x t r a c t e d w i t h e t h e r .  The  stirred  (40 mq, 0.26mmol)  the  potassium  a t room temper-  then a c i d i f i e d w i t h  to g i v e a crude o i l .  acetic  combined e t h e r e x t r a c t s  were washed w i t h r ^ O , sodium b i c a r b o n a t e , water, d r i e d and evaporated  mixture  (MgSO^),  D i s t i l l a t i o n under reduced pressure  afforded a clear o i l which was subjected to mass spectral analysis. • The mass s p e c t r a l peak of the undeuterated t o be  162,  found  w h i l e the mass s p e c t r a l p a r e n t peak o f the d e u t e r a t e d  compound was  found  to be 164.  e s t a b l i s h e d as the p r o d u c t in this  compound was  T h e r e f o r e , compound  ( a,3-unsaturated  (66)  was  ketone) formed  study.  Mol.Wt. c a l c d . f o r n i 2 2 c  mass s p e c t r o m e t r y ) ,  H  D  0  :  164.1164.  164.1170..  Found  (high r e s o l u t i o n  -105-  PART I I  SYNTHETIC STUDY ON ZIZAANE TYPE SESQUITERPENOIDS AND THE TOTAL SYNTHESIS OF (+) ISOLONGIFOLENE  INTRODUCTION  I.  GENERAL REMARKS Studies  very  instrumental  organic vealed class  chemistry the v a s t  i n the area o f terpene i n guiding as we  see i t today.  penoids, of  architectures present  chemist.  types,  As l a t e  a fact only  as 1953 o n l y  i n this  t o challenge the  The l a r g e s t g r o u p o f t e r -  the sesquiterpenoids, e x h i b i t s the g r e a t e s t  structural  decades.  T h e s e s t u d i e s have r e -  compounds w h i c h c o n t i n u e s  ingenuity of the organic  have been  t h e g r o w t h and d e v e l o p m e n t o f  array of molecular  of organic  chemistry  realized  about  i n the past  variation two  30 s e s q u i t e r p e n o i d  compounds  were known; by 1964 t h r e e h u n d r e d w e r e known, and b y 19 71 one  thousand d i f f e r e n t  This  s e s q u i t e r p e n o i d compounds h a d  r a p i d i n c r e a s e i n t h e number o f known  was p a r a l l e l e d by t h e a d v e n t o f new in the  the l a s t  three  decades.  detection, isolation  occurrence  and amines.  The f i f t e e n  so t h a t t h e s e s q u i t e r p e n e cyclic.  facilitated  demonstrated t h e i r  contain f i f t e e n  c a n be h y d r o c a r b o n s , a l c o h o l s , k e t o n e s ,  lactones  have  developed  wide-  i n nature.  Most s e s q u i t e r p e n o i d s and  sesquiterpenoids  and c h a r a c t e r i z a t i o n o f t h e h i t h e r t o  unknown p l a n t compounds and h a s t h u s spread  emerged.  a n a l y t i c a l techniques  These techniques  over  c a r b o n atoms  acids,  oxides,  c a r b o n atoms c a n b e  i s acyclic,  Because o f t h e f l e x i b i l i t y  arranged  mono, d i , t r i o r t e t r a -  i n the carbon  skeleton  -106-  combined w i t h not  the  variety  surprising that  class  of  nolepin  the  compounds a r e (108)  and  i n the  stereoselective  concerning  the as  reaction,  enolate  to the  as w i d e l y  the  the  the  complex m o l e c u l e s .  alkylations  c l a s s of  of  farnesol  structural  compounds any  Today a r i c h  (107),  (110), r e s e r p i n e  ver-  types synthetic  storehouse of  stereochemical course of  and  "Robinson  Diels-Alder  Application  l e d to the  Below a r e  (113).  as  (109).  a l d o l condensation,  organic chemist.  prostaglandins  differing  i t is  sesquiterpenoid  o r g a n i c c h e m i s t must n e c e s s a r i l y  approach.  k n o w l e d g e a v a i l a b l e has  chlorophyll  i n the  multiplicity  s t r u c t u r a l and  reactions  able  structures  sesquiterpenoid  s t r a t a g e m : u s e d by a  f u n c t i o n a l groups p o s s i b l e  longifolene  Because of found  of  four  of  successful  involve knowledge such  annelation" reaction  the  is  avail-  synthetic  synthesis  o f many  s u c h complex m o l e c u l e s ,  (111), c a r y o p h y l l e n e  (112)  and  the  -107-  -108-  Of play  an  the  numerous o r g a n i c  integral part  the  formation of  was  of  ketone.  in synthetic  involved  intramolecular  I t was  organic  carbon-carbon bonds.  i n t e r e s t t o us  bond v i a the  reactions  our  the  One  known, t h o s e  chemistry  a l k y l a t i o n of  an  acid of  natural products  isolongifolene  folene,  as w e l l  (117)  and  as  carbon-carbon  i n t e n t i o n t o employ s u c h a r e a c t i o n  f o r m e d i n t o a number o f n a t u r a l  cluded  a  which  ci^g-unsaturated  a s u i t a b l y f u n c t i o n a l i z e d molecule which could  The  involve  such r e a c t i o n  formation of  that  to  e a s i l y be  form  trans-  products. c h o s e n as  our  objective  in-  (114) , a r e a r r a n g e m e n t p r o d u c t o f l o n g i - -  zizanoic acid  khusimol  (118)  (115),  zizaene  which belong  (116),  to the  epizizanoic  zizaene  class  sesquiterpenes. II.  artefact  THE (+)  STRUCTURE AND PREVIOUS SYNTHESIS ISOLONGIFOLENE  The  fifteen  from the  c a r b o n atoms o f  acid catalyzed  isolongifolene,  rearrangement of  ( 1 0 9 ) , have b e e n shown t o be  a r r a n g e d as  (114).  The  i s o l o n g i f o l e n e was  Dev  co-workers  and  studies  44  structure  and  42  (+)  , using  finally  (109)  of  by  OF  spectroscopic  achieving  depicted  (114)  longifolene in  structure  determined  methods  its total  an  43  by  , degradation  synthesis  45  -109-  A s u c c e s s f u l s y n t h e s i s of  (+) i s o l o n g i f o l e n e  has  45 been r e p o r t e d by S. Dev of  .  The  first  step i n Dev's s y n t h e s i s  i s o l o n g i f o l e n e i n v o l v e d the treatment of camphene-l-carboxylie  acid  (119) with methyl l i t h i u m t o a f f o r d the methyl ketone  (119)  i n 83% y i e l d .  (120)  (120)  Condensation of the methyl ketone  (120) with  e t h y l cyanoacetate i n the presence o f ammonium a c e t a t e gave the  desired  d;6-unsaturated  ester  (121) i n 60% y i e l d .  a d d i t i o n of l i t h i u m d i m e t h y l c u p r a t e • to (121) a f f o r d e d  (120) a ' d i a s t e r o i s o m e r i c mixture i n 80% y i e l d .  T h i s mixture  Conjugate (122)  as  -110-  was h y d r o l y z e d u s i n g potassium y i e l d a single  hydroxide  c r y s t a l l i n e acid  The a c i d which, when t r e a t e d  (123) was  i n e t h y l e n e g l y c o l to  (123) .  converted i n t o i t s a c i d  w i t h S n C l ^ i n carbon  chloride  d i s u l f i d e a t -15° C  smoothly underwent i n t r a m o l e c u l a r a c y l a t i o n  to give c r y s t a l l i n e  a B -unsaturated ketone  The  }  ketone  (124) was  (124) i n 85% y i e l d .  a^-unsaturated  shown t o be i d e n t i c a l w i t h the . a B ;  unsaturated  ketone o b t a i n e d from the a . l l y l i c o x i d a t i o n o f i s o l o n g i f o l e n e . The above u n s a t u r a t e d ketone was converted i n t o the c o r r e s p o n d i n g dithioketal  (using ethane d i t h i o l and B F j E t 0 as c a t a l y s t ) . 2  The d i t h i o k e t a l was r e f l u x e d i n e t h a n o l to a f f o r d all  respects with  (+)  i n the presence o f Raney  nickel  a f t e r p u r i f i c a t i o n an alkene i d e n t i c a l i n isolongifolene.  -111-  III.  THE STRUCTURE AND PREVIOUS SYNTHESES OF SOME ZIZAANE-TYPE SESQUITERPENOIDS The zizaane group o f s e s q u i t e r p e n o i d s o f which  zizanoic acid khusimol  (115), zizaene  (118)^  the carbon  49,51  a  r  e  m  e  m  (116), e p i z i z a n o i c a c i d b  e  r  s f  n  a  s  (117) and  been shown t o have  s k e l e t o n as d e p i c t e d below.  c l a s s o f s e s q u i t e r p e n o i d s was determined  The s t r u c t u r e o f t h i s by a number o f r e s e a r c h  (115 ) R-^COOH, R„=H (116) R.=CH , R2=H (117) R7=H, R =COOH (118) Rj=CH OH, R =H 2  -112-  groups, using total  s p e c t r o s c o p i c methods and  synthesis. The  tricyclic  4 6  "  4 8  '  by  achieving  their  5 1  Zizaane-type  of sesquiterpenoids  contain  (6,2,l,0  undecane s y s t e m and  a number o f  syntheses of t h i s  l f 5  )  a  c a r b o n s k e l e t o n have a p p e a r e d i n t h e  successful liter-  52 ature. (116)  Coates e t a l . and  employed  synthesis, s i o n method  the  as  successfully synthesized the  key  step  (+)  zizaane  in their stereoselective  intramolecular diazoalkane-carbonyl  ring  expan-  ( 1 2 5 ) — * (126) .  (126)  Recently, has  an  intramolecular Diels-Alder reaction  been used t o s y n t h e s i z e  skeleton  5 3  (127)-»(128) +  a norsesquiterpene (129).  with  the  zizaane  -113-  Two of  o t h e r s u c c e s s f u l syntheses  s e s q u i t e r p e n o i d s both  o f the zizaane-type  involved a modified pinacol-type  rearrangement of a s u i t a b l y s u b s t i t u t e d t r i c y c l o undecane, such as (130).  (6,2,1,0^'^)  The d i f f e r e n c e between these two  sequences l i e s i n the s y n t h e s i s o f compound 48 et a l . s y n t h e s i z e d compound  (130a) from  (130a).  Yoshikoski  (+) camphenoic a c i d  (119a)  R l *2  (130a) R-^H, R =COOCH , R =MeSC> 2  3  3  (130b) R =COOCH , R =H, R =MeS0 1  3  i n the f o l l o w i n g manner. from the c o r r e s p o n d i n g  2  3  2  2  The b i c y c l i c a l c o h o l (119c),  acid  (119a) v i a i t s methyl e s t e r  obtained (119b),  was o x i d i z e d u s i n g d i c y c l o h e x y l c a r b o d i i m i d e and p h o s p h o r i c  (119a) R=H (119b) R=CH  (119c)  acid  (131)  3  i n d i m e t h y l s u l f o x i d e t o a f f o r d the aldehyde  (131) i n 80% y i e l d .  -114-  Condensation  of t h i s m a t e r i a l w i t h acetone i n the presence  sodium ethoxide gave the trans-dienone of  dienone  (132)  (132).  a f f o r d e d the keto n i t r i l e  Hydrocyanation  (133) which, upon  treatment w i t h ozone gave the d i k e t o n i t r i l e overall  of  (134)  i n 44%  yield.  (170)  u  When the d i k e t o n i t r i l e  (134) was  heated w i t h  2 e q u i v a l e n t s of b e n z o i c a c i d and p i p e r i d i n e i n benzene, the keto-nitrile  (17 1) was  formed i n 62% y i e l d .  T h i s m a t e r i a l was  reduced w i t h sodium borohydride and the r e s u l t i n g was  h y d r o l y z e d w i t h potassium hydroxide.  product was  The  hydroxy-nitrile  crude  reaction  then t r e a t e d w i t h diazomethane, f o l l o w e d by  Jones  54 oxidation  t o y i e l d the keto e s t e r  The k e t o - e s t e r (136) was  (136) i n 74% o v e r a l l  c o n v e r t e d i n t o the corresponding  yield.  -115-  COOCH.  CN  74% (171)  (136)  COOCH.  COOCH.  (135)  COOCH.  .(138)  COOH  (117)  COOR (139) R=CH. (140) R=H •  -116-  dithioketal to a f f o r d  (135) and s m o o t h l y d e s u l p h u r i z e d u s i n g Raney  the unsaturated  saturated ester (138). by  (137).  O x i d a t i o n o f t h e un-  (137) w i t h osmium t e t r o x i d e a f f o r d e d t h e d i o l  T h i s d i o l was  treatment  ester  nickel  transformed  into  the monomesylate  with methanesulfonylchloride.  The  (130a)  monomesylate 1 5  was  smoothly rearranged  i n t o the d e s i r e d t r i c y c l o  (6,2,1,0  ' )  undecane s k e l e t o n o f t h e z i z a e n e - t y p e o f s e s q u i t e r p e n o i d s by treatment  with potassium The k e t o  epizizanoic  acid  o f compound  (140).  zizaene  (139) was  (117) v i a a W i t t i g  been t r a n s f o r m e d and  ester  t-butoxide  i n t-butyl  subsequently reaction  Since e p i z i z a n o i c acid  into  zizanoic  acid  alcohol. converted  into  on t h e s o d i u m  salt  (117) has p r e v i o u s l y  (115), k h u s i m o l  (118)  (116) t h e above s y n t h e s i s o f e p i z i z a n o i c  acid  also  constitutes a formal synthesis of zizaene sesquiterpenoids (118)  (115)—  inclusively. Q  The f o l l o w i n g s y n t h e s i s o f t h e z i z a a n e g r o u p o f s e s quiterpenoids  involves a similar  above b u t d i f f e r s (130a). and  i n t h e method 46  Thus Ramage e t a l .  (130b) f r o m  (+)-camphor  the Grignard reagent a mixture silica  r e a r r a n g e m e n t as t h a t m e n t i o n e d o f p r e p a r a t i o n o f monomesylate  s y n t h e s i z e d monomesylate (141).  d e r i v e d from  of alcohols  (142a) and  Reaction o f the l a t t e r  (144) i n 81% y i e l d .  (142b) w h i c h upon t r e a t m e n t  with  afforded the  Birch reduction of this material  f o l l o w e d by i s o m e r i z a t i o n o f t h e crude  diene, using  p h o s p h i n e rhodjum  chloroform,  chloride  with  3 - b r o m o - 4 - m e t h o x y t o l u e n e gave  r e a r r a n g e d i n t o compound ( 1 4 3 ) . OsO.-NalO, t r e a t m e n t o f t h e l a t t e r 4 4  camphenilone  (130a)  i n refluxing  triphenyla f f o r d e d the  -117-  (142a) R ^ A R ,  R =OH  (142b) R-^OH, R =A 2  conjugated e n o l e t h e r a f f o r d e d compound the d i k e t o e s t e r ester  (143)  2  R  (202).  (203). (204).  Ozonolysis  o f (202) i n e t h y l  acetate  Jones o x i d a t i o n o f t h e l a t t e r gave Base c a t a l y z e d . c y c l i z a t i o n o f t h e d i k e t o  (204) u s i n g potassium t - b u t o x i d e  i n t-butyl alcohol afforded  COOCH  3  (136a)  I COOCH  COOCH_  (139a)  COOH  COOH (117)  (115)  -119-  a mixture o f t r i c y c l i c enones 3:2.  (136a) and (136) i n the r a t i o o f  T h i s mixture was separated  s i l i c a gel.  by column chromatography on  E q u i l i b r a t i o n o f (136) using potassium  t-butoxide  i n t - b u t y l a l c o h o l a f f o r d e d a mixture o f (136) and (136a) i n the r a t i o 2:3.  S i m i l a r r e s u l t s were o b t a i n e d  was e q u i l i b r a t e d .  Having separated  when compound  the keto e s t e r s  (136)  (136a) and  (136a) Ramage e t a l c o n v e r t e d each o f the e s t e r s i n t o the c o r r e s ponding, monomesylates  (130a) and (130b).  Rearrangement o f the  monomesylates a f f o r d e d the c o r r e s p o n d i n g ketones  (139a) and (139b)  1 5 having the r e q u i r e d  tricyclo  (6,2,1,0 ' ) undecane  skeleton.  These t r i c y c l i c ketones were then converted i n t o e p i z i z a n o i c acid  (117) and z i z a n o i c a c i d  (115) r e s p e c t i v e l y .  (115a)  Since already  the methyl e s t e r o f z i z a n o i c a c i d  been c o n v e r t e d i n t o khusimol  (115a) has  (118) and zizaene (116)  the above s y n t h e s i s  constitutes a t o t a l s t e r e o s p e c i f i c synthesis  of s e s q u i t e r p e n o i d s  (115) through t o (118).  The l a s t s u c c e s s f u l s y n t h e s i s i n v o l v e s the s y n t h e s i s  o f zizaene  i s o u t l i n e d below.  (173) was c o n v e r t e d i n t o the phenol  corresponding a l l y l ether  (174).  o f the l a t t e r a t 185°C a f f o r d e d  discuss  (115) by K. Wiesner e t a l .  The sequence employed i n t h i s s y n t h e s i s indanol  that I w i l l  5  1  The  (175), v i a the  Thus, a C l a i s e n rearrangement the phenol  (175).  Methylation  -120-  of the l a t t e r w i t h dimethyl s u l f a t e gave the methoxy d e r i v a t i v e (176).  Treatment of (176) w i t h sodium c h l o r a t e and a c a t a l y t i c  amount of osmium t e t r o x i d e a f f o r d e d the d i o l  (17 7).  Oxidative  cleavage of t h i s m a t e r i a l u s i n g sodium p e r i o d a t e gave the a l d e hyde  (178) which was k e t a l i z e d u s i n g ethylene g l y c o l and  t o l u e n e s u l f o n i c a c i d to a f f o r d the corresponding k e t a l  p—  (179).  B i r c h r e d u c t i o n of t h i s k e t a l and immediate a c i d c a t a l y z e d hy-  -121-  drolysis  of  the  (179)  resulting  O  0  ketone  Cyclization using  80% a c e t i c  acid  saturated ketones found  i n the  produced  :o I  of  the  afforded and  class  of  3,Y - u n s a t u r a t e d a mixture (182b)  of  having  ketone  the the  tricyclic  acetic  anhydride  and p y r i d i n e  skeleton  sesquiterpenoids.  (182b) (182b) was  (181),  e p i m e r i c , a,B-un-  (182a) RT=Me,  Alcohol  O  (181)  (181).  (182a)  zizaane  (180),  ( 1 8 0 )0 I  1  I  (^-unsaturated  dienol ether  acetylated  R]_=H,  R =H 2  R  2  = C H  3  using a mixture of  and t h e r e s u l t i n g  acetate  (183b)  was  -122-  smoothly  hydrogenated  i n e t h a n o l w i t h p a l l a d i u m - o n - c h a r c o a l to  f u r n i s h the keto a c e t a t e ^ (184b).  K e t a l i z a t i o n of t h i s m a t e r i a l  u s i n g e t h y l e n e g l y c o l and p - t o l u e n e s u l f o n i c a c i d d r o l y s i s of the r e s u l t i n g k e t a l Ketal  alcohol  (186b) was  f o l l o w e d by base  (185b),afforded the k e t a l  transformed i n t o the k e t a l  iodide.  OH  (188b) Pyrolysis  OXa  of the k e t a l xanthate  t i o n and d e k e t a l i z a t i o n  bromoacetate The  (186b)  (187b) dehydrogena-  of the r e s u l t i n g u n s a t u r a t e d k e t a l  a f f o r d e d the t r i c y c l i c ketone Alkylation  (187b) f o l l o w e d by  alcohol(186b  xanthate  (187b) by treatment w i t h carbon d i s u l f i d e and methyl  (188b)  (189b).  o f ketone  (189b) w i t h p y r o l i d i n e  f o l l o w e d by base h y d r o l y s i s  sodium s a l t of the keto a c i d  and  gave the k e t o a c i d  (190) was  treated  with  hy-  ethyl (190).  methylene,  \  -123-  (190b) t r i p h e n y l p h o s p h o r a n e t o a f f o r d the u n s a t u r a t e d c a r b o x y l i c (191b).  The a c i d  (191b) was  then s u b j e c t e d to the Simmons-  Smith c y c l o p r o p a n a t i o n c o n d i t i o n s u s i n g diiodomethane  with a  z i n c - c o p p e r couple to a f f o r d the t e t r a c y c l i c c a r b o x y l i c (192b).  Hydrogenation  acid  o f the l a t t e r over Adam's c a t a l y s t  a f f o r d e d the gem-dimethyl c a r b o x y l i c a c i d  The c a r b o x y l i c a c i d bromodecarboxylation  acid  (193b).  (193b) was then s u b j e c t e d to  c o n d i t i o n s , using,the m o d i f i e d  Hunsdiecker  method  , w i t h bromine and red m e r c u r i c oxide t o a f f o r d  t r i c y c l i c bromide  (194b).  Dehydrobromination  using  the  lithium  bromide and lithium carbonate in DMF afforded the tricyclic hydrocarbon (195) . An identical reaction sequence (182a)->(194a) afforded, after dehydrobromination of (194a), the tricyclic hydrocarbon (196).  A comparison of the hydrocarbons  (195) and (196)  to zizaene (116) revealed that both compounds (195) and (196) were isomers of zizaene (116). Epizizaene (196) was treated with osmium tetroxide and the resultant diol (197) was oxidatively cleaved using periodate to furnish ketone (198).  The  ketone (198) was epimerized in methanolic sodium methoxide to afford the ketone (199) with the natural stereochemistry.  The  ketone (199) was treated with methyl lithium which afforded a mixture of epimeric alcohols (200a) and (200b).  Acetylation  of this mixture using acetic anhydride in pyridine afforded the unstable acetates (201a) and (201b), which under the reaction conditions, (160°C, 60 h); pyrolyzed to give racemic zizaene (116).  -125-  (196)  (200a) (200b) (201a) (201b)  (197)  R =CH ,R =OH R =OH,R =CH Ri=CH ,R =OAC Ri=OAC,R2=CH 1  3  2  1  2  3  3  2  3  .  (  )  -126-  DISCUSSION I.  GENERAL APPROACH To be s u c c e s s f u l  it  i s often  useful  it  i s often  helpful  carefully bon  t o work t h e p r o b l e m  less  complex m o l e c u l e  functionalization  back i n t o  so t h a t  Furthermore first  stratagem  The c a r -  complex m o l e c u l e .  should possess the appro-  i t c o u l d be e a s i l y  the o r i g i n a l target molecule.  synthetic  molecules  c a n t h e n be s i m p l i f i e d b y  " b r e a k i n g " bonds t o form a l e s s  structurally  priate  backward.  t o b e g i n t h e s y n t h e t i c p l a n by  skeleton o f the target molecule  The  o f complex  s t u d y i n g a m o l e c u l a r m o d e l o f t h e compound.  theoretically  of  i n the synthesis  reassembled  Examples o f t h i s  type  and m e t h o d o l o g y c a n be f o u n d i n t h e 22  literature. (51)  The  used  Kelly  this  theoretical  et a l  general  , i n their  synthesis  o f (+)  ishwarane  approach.  " b r e a k i n g " o f t h e Cp-C,- b o n d i n (+) i s h w a r a n e  (51)  -127-  produced a s i m p l i f i e d t r i c y c l i c ishwarane.  structure  (49) as  compared-.with  The a p p r o p r i a t e l y f u n c t i o n a l i z e d i n t e r m e d i a t e  (49)  underwent an i n t r a m o l e c u l a r a l k y l a t i o n r e a c t i o n t o form the t e t r a c y c l i c s k e l e t o n of ishwarane.  A s i m i l a r approach, was  used i n our s y n t h e s i s of (+) i s o l o n g i f o l e n e (114)* zizaane-type  and o f the  sesquiterpenoids.  (114)  At the o u t s e t o f t h i s p r o j e c t i t was our i n t e n t i o n t o c o n s t r u c t the t r i c y c l i c  carbon s k e l e t o n o f i s o l o n g i f o l e n e (114) v i a an  i n t r a m o l e c u l a r a l k y l a t i o n r e a c t i o n o f an a .$ -unsaturated Upon a n a l y z i n g  ketone.  the s t r u c t u r e o f i s o l o n g i f o l e n e i t becomes c l e a r  t h a t the t h e o r e t i c a l "breaking"  o f the  to a much s i m p l e r b i c y c l i c i n t e r m e d i a t e  (144b)  *  bond would (144b).  This  (144a)  •Numbering system taken from paper by S. Dev e t a l  lead intermediate  -128-  when p r o p e r l y f u n c t i o n a l i z e d should c l e a r l y resemble (144a). mediate  compound  In f a c t the compound chosen as the s y n t h e t i c was keto t o s y l a t e  (144).  I t appeared  inter-  t o be an a t t r a c t i v e  TsO  c h o i c e f o r a number o f reasons. simple decalone system an extended  Firstly,  i t was a r e l a t i v e l y  (ignoring stereochemistry).  d i e n o l a t e anion c o u l d be generated  at the Cg p o s i t i o n .  Secondly,  specifically  T h i r d l y , m o l e c u l a r models o f keto t o s y l a t e  (144).) i n d i c a t e d t h a t when i n an a p p r o p r i a t e conformation, i h a boat conformation) , C-, and  C  c  (B r i n g  are i n very c l o s e p r o x i m i t y .  (144c) (165)  F o u r t h l y , the l e a v i n g group  i s l o c a t e d on a primary carbon atom  and hence s h o u l d be e a s i l y d i s p l a c e d .  F i n a l l y , the r e c o n s t r u c t i o n  of the t r i c y c l i c s k e l e t o n o f i s o l o n g i f o l e n e would be accomplished  -129-  via  the i n t r a m o l e c u l a r a l k y l a t i o n of an a B-unsaturated  ketone.  I f and when o c t a l o n e (165) i s prepared i t should be "easy" to introduce  two t e r t i a r y methyl groups v i a the f o l l o w i n g four  step  sequence.  U68) A t t h i s p o i n t i t i s p e r t i n e n t t o focus specifically  upon compound  (166).  a t t e n t i o n more  T h i s compound i s s u i t a b l y CN  2) f u n c t i o n a l i z e d f o r the i n t r o d u c t i o n of a n i t r i l e  functionality  -130-  at the  position.  successful both.  I f hydrocyanation  i t s h o u l d form  compound  o f dieneone  (171) o r compound  I t i s not important which n i t r i l e  corresponding esters,  compound  (172) o r  i s formed s i n c e t h e  (136) and ( 1 3 6 a ) ,  (136)  have b e e n  I f a,$-unsaturated  i s the product o f hydrocyanation o f dienone  keto n i t r i l e  (171)  (166) then formation  (171) w i l l c o n s t i t u t e a formal s y n t h e s i s o f the above  mentioned zizaane-type s e s q u i t e r p e n e s f o r the f o l l o w i n g Firstly,  shown  • (136a)  to be i n t e r c o n v e r t i b l e .*°  o f compound  (166) i s  a B-unsaturated ;  keto n i t r i l e  reasons.  (171) has a l r e a d y been  transformed, v i a the <x Br u n s a t u r a t e d keto e s t e r ;  (136), i n t o  48 epizizanoic acid  (117)  .  Secondly, the l a t t e r compound has been  transformed i n t o z i z a n o i c a c i d khusimol  (116) and  (118). If,  on the o t h e r hand, the n i t r i l e group i s i n t r o -  duced from the 6-face it  (115), zizaene  t o form a B - u n s a t u r a t e d keto n i t r i l e (172) y  i s o n l y important t o c o n v e r t the a,$—unsaturated  (172) i n t o the corresponding methyl e s t e r 46 reasons.  Ramage e t a l  keto  nitrile  (136a) f o r the f o l l o w i n g  have shown t h a t ar& -unsaturated keto  (116)  -132-  ester  (136a) can be r e a d i l y transformed i n t o z i z a n o i c  (17 2)  acid  (136a)  (115).  (115)  Secondly, Ramage e t a l have demonstrated that base  catalysed  e q u i l i b r a t i o n of e i t h e r -.-a,J3-'unsaturated keto e s t e r  (136) o r  (136a) r e s u l t s i n a mixture of a,3-unsaturated keto e s t e r s and  (136a) .  (136a) 2  '(136) 3  (136a) 2  (136) 3  (136)  -133-  II.  TOTAL SYNTHESIS OF The  (±) ISOLONGIFOLENE *  s t a r t i n g m a t e r i a l chosen  tosylate  (144) was o c t a l o n e  f o r the s y n t h e s i s o f keto  (97). Octalone  (97) was  prepared  57 by  a known  ical lone  (97) was d i a l k y l a t e d  t-butoxide  (146).  absorptions  the assigned  singlet  t o g i v e an 80%  The i n f r a r e d a t 1730 c m  a triplet  a t 6=3.75  a s i x proton  protons  structure.  yield  The  - 1  spectrum o f octalone a n d 1710 cm  1  singlet  o f t h e two t e r t i a r y  methyl  (146) showed carbonyl  readily  proton,  and a  o f the e s t e r group  attributed  t o the  groups.  (146)  saturated ring  side chain.  struc-  The ^H N.M.R. s p e c t r u m  methyl protons  a t 6 =1.15  of 58  (146).  due t o t h e e s t e r  a t 6 a5.9 0 due t o t h e v i n y l  due t o t h e  used as a "handle"  ~  Octa-  of octalone  (97)  bon  and p h y s -  using methyl i o d i d e i n the presence  saturated carbonyl respectively.  exhibited  and  and showed s p e c t r a l  p h y s i c a l a n d s p e c t r a l p r o p e r t i e s were i n a c c o r d w i t h  ture  and  procedure  p r o p e r t i e s i n accord with  potassium The  literature  carbonyl of octalone  (146) was  next  f o r t h e i n t r o d u c t i o n o f t h e r e q u i r e d one c a r -  As e x p e c t e d  the W i t t i g  reaction occurred  The total sequence i s outlined on the next page.  -134-  (114)  -135-  c h e m i o s p e c i f i c a l l y a t the more r e a c t i v e s a t u r a t e d r i n g  carbonyl  59 site.  Thus, treatment  of octalone  of methylene triphenylphosphorane  (146) w i t h four e q u i v a l e n t s  i n dimethyl  s u l f o x i d e a t room  temperature f o r 1.5 hours a f f o r d e d , a f t e r p u r i f i c a t i o n , (147)  as an o i l i n 82% i s o l a t e d  yield.  (146)  The (147). and  diene  (147)  p h y s i c a l and s p e c t r a data were i n accord w i t h s t r u c t u r e The i n f r a r e d spectrum e x h i b i t e d a b s o r p t i o n s  890 c m  1  a t 1635 cm  1  due t o the two double bonds and a l s o showed t h e  l a c k o f an a b s o r p t i o n a t 1710 cm  1  due t o any s a t u r a t e d  p r e s e n t i n the s t a r t i n g m a t e r i a l , o c t a l o n e  (146).  carbonyl  The  N.M.R.  spectrum e x h i b i t e d an a b s o r p t i o n a t 6=5.80 due t o the v i n y l proton o f the t r i s u b s t i t u t e d double bond, an a b s o r p t i o n a t 6=4.70 due t o the two v i n y l protons a multiplet,  a s i n g l e t at -6 = 3.60  o f the exomethylene group as  due t o the methyl e s t e r  and  two s i n g l e t s at6=1.10 and.6-1.24 due t o the protons  two  t e r t i a r y methyl groups.  protons o f the  -136-  In o r d e r t o complete carbon  chain of keto t o s y l a t e  selectively  hydroborated  t r a n s f o r m a t i o n was  f o l l o w e d by using  accomplished  The  o f the i n t e r m e d i a t e  and  structures  (148)  on  columns i n d i c a t e d  several  Separation spectral the  two  Since the  (149).  6 0  spectral  was  .  regio-  This in  latter  THF  trialkylborane  a mixture  of  of alcohols  compounds (148)  d a t a were i n a c c o r d w i t h  A G.L.C. a n a l y s i s o f t h i s m a t e r i a l the presence  o f two  compounds.  o f t h i s m a t e r i a l by p r e p a r a t i v e G.L.C. f o l l o w e d by  a n a l y s i s o f each  individual  compounds were i n f a c t  the  to y i e l d  an e p i m e r i c m i x t u r e  physical and  (147)  using disiamylborane  hydrogen p e r o x i d e  p r e s u m e d t o be  (149).  (144), the d i e n e  a t the exomethylene s i t e  decomposition  alkaline  t h a t was and  t h e c o n s t r u c t i o n o f t h e r e q u i r e d one  N.M.R. s p e c t r u m  c o r r e c t number o f p r o t o n s  component, r e v e a l e d t h a t  the a l c o h o l  (149)  and  of the o r i g i n a l mixture (as d e t e r m i n e d  l a c t o n i z a t i o n must have o c c u r r e d on  by  lactone  (150).  exhibited  integration)  t h e c o l u m n d u r i n g t h e G.L.C.  -137-  analysis.  That the h y d r o b o r a t i o n  specifically  r e a c t i o n took p l a c e r e g i o -  a t the exomethylene s i t e was e v i d e n t from the  N.M.R. s p e c t r a o f both  the t r a n s - a l c o h o l (149)  and the l a c t o n e  (150).  The "^H N.M.R. spectrum o f the l a c t o n e  triplet  a t 6=5.80 ( v i n y l proton region) which i n t e g r a t e d f o r  one  proton.  The  triplet  (149)  (6—5.72) i n the v i n y l  The above data c l e a r l y e l i m i n a t e d the  that hydroboration  showed a  N.M.R. spectrum o f the t r a n s - a l c o h o l  a l s o e x h i b i t e d a one proton ton r e g i o n .  (150)  pro-  possibility  had o c c u r r e d a t the t r i s u b s t i t u t e d double  bond t o form compounds  (151)  o r (152).  0  (152)  (151) The  assignment o f the s t e r e o c h e m i s t r y  o f the hydroxymethyl  s i d e c h a i n i n (149) was based on a t h e o r e t i c a l c o n s i d e r a t i o n o f the f o l l o w i n g r e a c t i o n s . hydroboration had  Of the two a l c o h o l s formed d u r i n g  r e a c t i o n (148)  and (149), only the  the r e q u i r e d s t e r e o c h e m i s t r y  the  cis-isomer  for lactonization.  Therefore,  the a l c o h o l i s o l a t e d by p r e p a r a t i v e G.L.C. must have been the trans-alcohol  (149).  The i n f r a r e d spectrum o f a l c o h o l  showed the presence o f a hydroxy1 f u n c t i o n a t 34 50 cm  1  (149) and an  -138-  e s t e r c a r b o n y l a b s o r p t i o n a t 1720 cm exhibited a due  triplet  . The H N.M.R. spectrum  a t £-5.72 ( t , I H , v i n y l ) , a s i n g l e t at 5 =3.66  t o the methyl e s t e r protons,  and a p a i r o f s i n g l e t s a t  6=1.01 and ^1.07 due t o the two t e r t i a r y methyl groups. The  i n f r a r e d spectrum o f l a c t o n e  t i o n a t 1720 c m due  - 1  due t o the l a c t o n e c a r b o n y l and no a b s o r p t i o n  t o any h y d r o x y l  triplet  group.  The "^H N.M.R. spectrum e x h i b i t e d a  a t 6=5.80 due t o the v i n y l proton,  a t '6=1.12 due t o the protons no a b s o r p t i o n  f o r the protons  of an ABX p a t t e r n centered protons The  (150) e x h i b i t e d an absorp-  a singlet  o f the two t e r t i a r y methyl groups, o f a methyl e s t e r , and the AB p a r t  a t 6=4.16 and 6 =4.56 due t o the two  on the s i d e c h a i n carbon atom i n the l a c t o n e next stage  absorption  i n the s y n t h e s i s o f the keto  ring.  tosylate  (144)  r e q u i r e d the i n t r o d u c t i o n o f a c a r b o n y l group a t the C-3 p o s i t i o n o f compounds  (148) and (149) v i a an a l l y l i c o x i d a t i o n  by t h e removal o f the carbomethoxy group.  followed  However, b e f o r e the  COOCH  (144)  (148) (149)  f i r s t requirement c o u l d be met the h y d r o x y l  group had t o be  p r o t e c t e d s i n c e i t would n o t s u r v i v e the a l l y l i c o x i d a t i o n s t e p . Thus, treatment o f the o l e f i n i c a l c o h o l s  (148) and (149) w i t h  -139-  a mixture o f a c e t i c anhydride and p y r i d i n e f o r 18 hours a t room temperature a f f o r d e d an e p i m e r i c mixture o f the d e s i r e d acetates  (153) and (154) i n 97% y i e l d .  An a n a l y t i c a l sample  • (153)  (154)  of each o f the c i s and t r a n s - a c e t a t e s was o b t a i n e d by p r e p a r a t i v e G.L.C. (10% O.V.17).  The s p e c t r a l p r o p e r t i e s o f each  isomer was i n a c c o r d w i t h the a s s i g n e d s t r u c t u r e s .  Of p a r t i c u l a r  i n t e r e s t was the absence o f h y d r o x y l a b s o r p t i o n s i n the i n f r a r e d spectrum.  The  N.M.R. o f the r e s p e c t i v e a c e t a t e s  (153) and  (154) e x h i b i t e d a c e t a t e methyl proton resonances as s i n g l e t s a t 6=2.00 ( t r a n s - a c e t a t e ) and 6=2.04  (cis-acetate).  To e s t a b l i s h which isomer was c i s and which isomer was t r a n s , the  N.M.R. spectrum o f each a c e t a t e was compared w i t h  t h a t o f the t r a n s - a l c o h o l of a l c o h o l s  (149) .  The "''H N.M.R. o f the mixture  (148) and (149) as w e l l as the ''"H N.M.R. spectrum  of the mixture o f a c e t a t e s  (153) and (154) both e x h i b i t e d the  same p a t t e r n due t o t e r t i a r y methyl p r o t o n s , which appeared as four s i n g l e t s .  Of the f o u r s i n g l e t s , two were due t o the t r a n s -  isomer and two were due t o the c i s - i s o m e r • p a t t e r n s are shown below.  The methyl  signal  -140-  ;  Mixture o f a l c o h o l s (148)-& (149)  trans-Alcohol  (149)  Mixture o f a c e t a t e s (153) & (154) trans-Acetate  (153)  c i s - A c e t a t e (154)  1.0  2.0 6  '  0.0  6  The  acetate  epimer which possessed the same p a t t e r n due t o  the methyl s i g n a l s as was found f o r the t r a n s - a l c o h o l t e n t a t i v e l y assigned  the t r a n s - s t e r e o c h e m i s t r y  (153).  (149) was To con-  f i r m the above assignment a s m a l l sample o f the t r a n s - a c e t a t e (153)  was s u b j e c t e d  t o base h y d r o l y s i s .  The r e s u l t i n g a l c o h o l  was found t o be i d e n t i c a l w i t h the t r a n s - a l c o h o l from the h y d r o b o r a t i o n the  reaction.  (149) o b t a i n e d  This l a t t e r r e s u l t  confirmed  above assignments f o r the c i s and t r a n s - a c e t a t e s . The  mixture o f a c e t a t e s  C o l l i n s oxidation conditions^*  (153) and (154) was s u b j e c t e d t o 1  group a t the a l l y l i c p o s i t i o n .  i n order  to introduce  Although the C o l l i n s  a carbonyl oxidation  procedure was somewhat s u c c e s s f u l , p r o v i d i n g a mixture o f o c t a -  -141-  NBS,CaCC>3 —+  lones  (155)  +  (156)  (155) and (156) i n 70% y i e l d * , a higher y i e l d i n g  o x i d a t i o n method was sought due t o the d i f f i c u l t y the s e p a r a t i o n o f s t a r t i n g m a t e r i a l from product.  allylic  involved i n Thus,  62 f o l l o w i n g the procedure (153)  o f Thomson e t a l  a mixture  of a c e t a t e s  and (154) was t r e a t e d w i t h N-bromosuccinimide i n aqueous  dioxane, light.  and the r e s u l t a n t mixture was i r r a d i a t e d w i t h T h i s procedure  a f f o r d e d a mixture  of o c t a l o n e s  visible (155)  and  (156) i n 96% y i e l d .  An a n a l y t i c a l sample o f both the c i s  and  t r a n s isomers were o b t a i n e d by p r e p a r a t i v e G.L.C. (10% O.V.17).  The  s p e c t r a l p r o p e r t i e s of the o c t a l o n e s  i n accord w i t h the a s s i g n e d s t r u c t u r e s . spectrum showed an cx^ 8-unsaturated  (155) and (156) were Thus the i n f r a r e d  c a r b o n y l a b s o r p t i o n a t 1660 cm  •based on recovered s t a r t i n g m a t e r i a l  1  and  1670 cm  The  "''H N.M.R. spectrum o f the t r a n s - o c t a l o n e  x  f o r octalones  (155)  and (156)  respectively. (155)  exhibited a  s i n g l e t at 6=6.22 due t o the v i n y l proton and the spectrum o f the c i s - o c t a l o n e to the v i n y l The  (156)  a l s o e x h i b i t e d a s i n g l e t at 6=6.22 due  proton.  mixture o f o c t a l o n e s  (155)  and (156)  upon being  sub-  63 j e c t e d t o decarbomethoxylation c o n d i t i o n s excess o f l i t h i u m bromide i n HMPA a t 140° afforded,  after d i s t i l l a t i o n ,  using  a five  fold  f o r four hours,  a c l e a r o i l i n 79% y i e l d .  A  G.L.C. a n a l y s i s of t h i s o i l i n d i c a t e d the presence o f three compounds.  The s p e c t r a l data o f the mixture i n d i c a t e d t h a t no a c i d  functionality present  (I.R.) o r e s t e r f u n c t i o n a l i t y (^H N.M.R.) was  and thus s t r o n g l y suggested t h a t the three  were o c t a l o n e s  (157),  (158)  compounds  and (159) . H  K e t a l i z a t i o n o f the above crude keto a c e t a t e ethylene  mixture  using  g l y c o l i n the presence o f a c a t a l y t i c amount o f p - t o l u -  e n e s u l f o n i c a c i d a f f o r d e d the c r y s t a l l i n e k e t a l  (160), m.p.  -143-  101-102°C i n 87% y i e l d .  Compound (160) e x h i b i t e d  absorbances  (160) i n i t s i n f r a r e d spectrum and  a t 1220 c m  spectrum  - 1  a t 1725 cm  due t o the a c e t a t e c a r b o n y l  due t o C-0 bond s t r e t c h i n g s .  of ketal  The H N.M.R. 1  (160) showed a s i n g l e t a t 6-3.92 due t o the  e t h y l e n e k e t a l protons; and a m u l t i p l e t c e n t e r e d at 6-4.00 due to the protons on the carbon b e a r i n g the a c e t a t e f u n c t i o n . N.M.R. spectrum  a l s o showed a s i n g l e t a t 6=2.00 which was  r e a d i l y a s s i g n a b l e t o the a c e t a t e methyl protons methyl s i g n a l s a t 6=1.03 and 6=0.87.  reduction of k e t a l acetate  and 2 quaternary  The above s p e c t r a l data  was i n complete agreement w i t h s t r u c t u r e The  The  (160).  (160) t o the k e t a l  alcohol  (161) was a c h i e v e d by u s i n g l i t h i u m aluminum h y d r i d e i n THF. The  s p e c t r a l data o f the r e s u l t i n g a l c o h o l  a c c o r d w i t h i t s proposed  structure.  (94% y i e l d ) were i n  The presence  group was e v i d e n t due t o an a b s o r p t i o n a t 3350 cm red spectrum.  The  N.M.R. spectrum  o f an h y d r o x y l 1  i n the i n f r a -  o f k e t a l a l c o h o l (161)  e x h i b i t e d a f o u r p r o t o n s i n g l e t a t 6=3.95 due t o the e t h y l e n e k e t a l p r o t o n s , and 2 s i n g l e t s a t 6= 1.03 and 6= 0.82 due t o the two  t e r t i a r y methyl p r o t o n s .  -144-  (161)  Ketal  alcohol  (162)  (161) was  next converted i n t o the k e t a l  tosylate  (162) by the a c t i o n o f p - t o l u e n e s u l f o n y l  pyridine  at room temperature  cooling  f o r 12 hours.  99% y i e l d .  The  informative,  lets  The  an &2*2  $=3.90) due  (6=2.42) due  (6=0.95 and  the absence  structure  of a h y d r o x y l a b s o r p t i o n  P  a  t  t  e  r  n  ^  u e  t  o  t  n  e  aromatic pro-  to the e t h y l e n e k e t a l p r o t o n s , a  to the aromatic methyl group and two  6=0.79) a t t r i b u t e d to the t e r t i a r y methyl  The c r u c i a l keto t o s y l a t e s now  (162) i n  N.M.R. spectrum, which was p a r t i c u l a r l y  exhibited  tons, a s i n g l e t  needles of keto t o s y l a t e  s p e c t r a l data were i n agreement w i t h  Of importance was  i n the i n f r a r e d .  singlet  crude product upon  c r y s t a l l i z e d to y i e l d a f t e r r e c r y s t a l l i z a t i o n , from  petroleum-ether/acetone,white  (162).  The  chloride in  (144) and  be o b t a i n e d from k e t a l t o s y l a t e  (16 3) or both  (162) by simply  singgroups.  could  removing  the e t h y l e n e k e t a l group and thus r e g e n e r a t i n g the c a r b o n y l group. Thus, k e t a l t o s y l a t e  (162) upon treatment w i t h a c a t a l y t i c  amount of c o n c e n t r a t e d s u l f u r i c a c i d i n aqueous acetone a t 50° C  (163)  (162) H  (144)' f o r 0.75 hours a f f o r d e d keto t o s y l a t e  (163) i n g r e a t e r than  99% y i e l d .  The s p e c t r a l data w a s . c o n s i s t e n t w i t h the a s s i g n e d  structure.  The i n f r a r e d spectrum  cm  1  e x h i b i t e d an a b s o r p t i o n a t 1715  due t o the s a t u r a t e d c a r b o n y l group.  Although  a l s o e x h i b i t e d a weak a b s o r p t i o n a t 1660 cm  1  the i n f r a r e d  no v i n y l p r o t o n  due to an a B - u n s a t u r a t e d ketone was d e t e c t e d i n the "*"H N.M.R. ;  spectrum.  The "*"H N.M.R. spectrum  e x h i b i t e d and &2 2 X  P  a t t e r n  (6-7.3 and 6 7.7) due t o the aromatic p r o t o n s , a m u l t i p l e t =  (6=3.85)  due t o the two protons on the carbon atom b e a r i n g the t o s y l a t e group,  a singlet  two s i n g l e t s groups.  (J = 2.42)  due t o the aromatic methyl  (.6=0.70 and 6=0.60) due t o the t e r t i a r y  That keto t o s y l a t e  was d i f f e r e n t  group, and methyl  (163) o b t a i n e d i n the l a t t e r  from the " d e s i r e d " keto t o s y l a t e  reaction  (144) was o f no  consequence s i n c e d u r i n g the c r u c i a l c y c l i z a t i o n step both t o s y -  -146H  (165)  l a t e s must form the same extended  d i e n o l a t e anion  Having thus o b t a i n e d the keto t o s y l a t e (proposed)  (164).  (163) the c r i t i c a l  i n t r a m o l e c u l a r c y c l i z a t i o n of (163) t o form the t r i -  c y c l i c s k e l e t o n o f (+) i s o l o n g i f o l e n e  (114) c o u l d now be t e s t e d ,  and was, i n f a c t , found t o be extremely f a c i l e . of the keto t o s y l a t e room temperature  Thus treatment  (163) w i t h potassium t - b u t o x i d e i n HMPA a t  f o r 15 minutes a f f o r d e d , a f t e r  recrystallization  the t r i c y c l i c o c t a l o n e (165) as white c r y s t a l s m.p. 63-64° C i n 64%  isolated yield.  The s p e c t r a l data were i n a c c o r d w i t h the  a s s i g n e d s t r u c t u r e f o r o c t a l o n e (165) .  The "''H N.M.R. spectrum  e x h i b i t e d a sharp s i n g l e t a t <S=5.72 r e a d i l y a t t r i b u t e d t o the v i n y l proton and a s i x proton s i n g l e t a t 6=1.36 due t o the two  -147-  (165) tertiary  methyl groups.  a 6 -unsaturated ;  The i n f r a r e d  c a r b o n y l a b s o r p t i o n a t 1670 c m  d a t a was i n c o m p l e t e a g r e e m e n t w i t h Having required all  synthesized octalone  functionality  structure  (165)  e x h i b i t e d an - 1  .  The s p e c t r a l  (165).  which possessed t h e  i n t h e B - r i n g o f (±) i s o l o n g i f o l e n e (114)  t h a t r e m a i n e d was t o i n t r o d u c e 2 t e r t i a r y m e t h y l g r o u p s a t  C - l and t o remove t h e c a r b o n y l  The the  spectrum  i n t r o d u c t i o n o f b o t h m e t h y l g r o u p s was a c c o m p l i s h e d  conjugate  saturated  group.  addition of lithium  cross conjugated  d i m e t h y l cup r a t e  dienone.  introduction  t o a n ci^B - u n -  Thus t h e f i r s t  l a s t p a r t o f t h e s y n t h e s i s o f (±) i s o l o n g i f o l e n e  by  step i n the  required the  o f a n o t h e r d o u b l e bond in ring A of octalone (]65).  T h i s was a c c o m p l i s h e d  by u s i n g d i c h l o r o d i d y a n o q u i n o n e  (DDQ)  64  -148-  Thus t r e a t m e n t in  refluxing  afforded,  of octalone  dioxane  (165) w i t h  containing acetic  after purification  crystalline  acid  f o r 17  hours,  and r e c r y s t a l l i z a t i o n  leum e t h e r , t h e c r o s s c o n j u g a t e d white  1.5 e q u i v a l e n t s o f DDQ  compound m.p.  ketone  from  petro-  (166) i n 60% y i e l d  as a  72-73°C.  (166) The  spectral  d a t a were i n a c c o r d w i t h  infrared  spectrum  exhibited  and  1601 cm"  spectrum  1  -  1 2  ( J  =10  a t 6=6.30  assigned  to the v i n y l protons.  23  =2  HZ,  centered  a t 6=1.06 a n d  6  to produce  J  =  ondary  olefinic  addition  site  over  - 1  The "*"H N.M.R. Hz, I H ) , a  H  z  '  w  n  ich  were  dienone  methyl  (166) was  readily singlets  groups.  treated  with  a r e g i o s p e c i f i c methylation occurred  the o^g-unsaturated  the conjugate  cm  1  A l s o p r e s e n t were two  ketone  r e s u l t was n o t a l t o g e t h e r u n e x p e c t e d that  ( J _ ,=2  6=1.11 due t o t h e q u a t e r n a r y  dimethylcuprate ^  The  IH) a n d a d o u b l e t o f d o u b l e t s  Hz, ^ 2 1 0  When t h e c r o s s c o n j u g a t e d lithium  dienone.  a doublet a t 6=5.99  a t J6=7.02 ( J  doublet  (166).  a b s o r p t i o n s a t 1660 cm ' ', 1630  f o r the cross conjugated  exhibited  structure  (167) i n 88% y i e l d . since  i t has been  of cuprate reagents w i l l  a similar  tertiary  olefinic  This  shown  favor a secsite. ^ 6  -149-  (166)  r The s t e r e o c h e m i s t r y of the r e c e n t l y i n t r o d u c e d methyl group was  a s s i g n e d w i t h the h e l p o f m o l e c u l a r models.  These  models suggested t h a t the approach o f a cuprate reagent from the a face would be s e v e r e l y h i n d e r e d by the two carbon b r i d g e 0  whereas an a t t a c k by the reagent on the g face would encounter l e s s s t e r i c hindrance from the one carbon b r i d g e . The i n f r a r e d spectrum of o c t a l o n e at 1650  cm"  1  and 1640  cm  1  (167) showed a b s o r p t i o n s  due t o the a,3 -unsaturated ketone.  The H N.M.R. spectrum e x h i b i t e d a s i n g l e t a t 6 =5.72 (IH) due 1  to the v i n y l p r o t o n , two s i n g l e t s at <5=1.12 and<5-1.08 a t t r i b u t e d to the two t e r t i a r y methyl groups and a d o u b l e t atgj =1.02  (J=8  Hz)  due to the secondary methyl group. The above 2 step sequence was  now  r e p e a t e d on o c t a l o n e  (167)  i n the hope o f i n t r o d u c i n g a second methyl group a t C - l . Howe v e r , treatment of o c t a l o n e  (167) w i t h DDQ,  under a v a r i e t y of  c o n d i t i o n s , a f f o r d e d a very poor y i e l d of dienone another s y n t h e t i c sequence was  (169) and  attempted.  The d i f f i c u l t i e s encountered i n the dehydrogenation o f octalone  (167) were overcome when a bromination-dehydrobromination  sequence proved somewhat s u c c e s s f u l .  Thus b r o m i n a t i o n of  (168)  0  O  (167) octalone THF  (169)  (167) u s i n g p y r i d i n i u m hydrobromide perbromide  66  in  c o n t a i n i n g a c e t i c a c i d a t 45°C f o r one hour a f f o r d e d the crude  bromooctalone  (16 8).  Because o f the u n s t a b l e nature o f the crude  bromooctalone m i x t u r e , (as i n d i c a t e d by decomposition d u r i n g distillation)  i t was dehydrobrominated without p u r i f i c a t i o n .  Thus, the crude bromooctalone upon treatment w i t h a l i t h i u m 67 b r o m i d e - l i t h i u m carbonate mixture i n d i m e t h y l formamide 1 4 0 C f o r 3 ho urs  a f f o r d e d , a f t e r column chromatography  w  gel),  dienone  (169) i n 40% y i e l d .  agreement w i t h s t r u c t u r e  (169).  a b s o r p t i o n s a t 1660 cm \ dienone. ^ l J  2  = 2  H z  .at (silica  The s p e c t r a l data were i n The i n f r a r e d spectrum e x h i b i t e d  1630 cm  1  due t o the c r o s s conjugate  The H N.M.R. spectrum e x h i b i t e d a d o u b l e t a t 6=6.00 1  ^  d  u  e  t  o  t  h  e  v  ^ Y n  1  p r o t o n marked H^ and a p a i r o f  o v e r l a p p i n g d o u b l e t s c e n t e r e d a t 6=6.14 (J=2 Hz) due to the v i n y l p r o t o n marked H,,.  The v i n y l methyl s i g n a l a t 6=2.00 (J=2 Hz)  appeared as a sharp d o u b l e t (J=2 Hz) undoubtedly due t o a l l y l i c coupling to H2. at  The t e r t i a r y methyl groups appeared as s i n g l e t s  6=1.10 and $=1.20.  -151-  (169) Although  the bromination-dehydrobromination  poor y i e l d i n g , enough m a t e r i a l was the f i n a l methyl the dienone  f o r 5 hours  40% y i e l d . *  The  of  dimethylcuprate  a f f o r d e d a f t e r chromato(124), m.p.  53-54°c  s p e c t r a l data were i n g e n e r a l agreement w i t h  O  (124)  *based  accomplish  Thus treatment  (169) w i t h 5 e q u i v a l e n t s of l i t h i u m  graphy, a pure c r y s t a l l i n e sample of o c t a l o n e in  i  s y n t h e s i s e d to  cuprate a d d i t i o n r e a c t i o n .  i n e t h e r at room temperature  sequence was  on r e c o v e r e d s t a r t i n g m a t e r i a l  (  -152-  the  literature  singlet  values.**  3  groups.  Comparing  and 4 s i n g l e t s a t  and 6 = 1.14 due t o t h e f o u r t e r t i a r y  these  chemical  s h i f t s with  methyl  the l i t e r a t u r e indicated  (170) s y n t h e s i z e d b y t h e above s e q u e n c e was i n d e e d  same a s t h e o c t a l o n e  total  proton  exhibited a  o f 6=5.67, 6=0.99, 6=1.03, 6 =1.08 and 6=1.15  that octalone the  X  a t 6=5.70 due t o t h e v i n y l  6=1.00, 6=1.05, 6. =1. 09,  values  The H N.M.R. s p e c t r u m  45 s y n t h e s i z e d b y S. Dey e t a l  i n their  s y n t h e s i s o f (±) i s o l o n g i f o l e n e . * The  synthesis  last  chemical  o p e r a t i o n needed t o complete  o f (+) i s o l o n g i f o l e n e ,  group o f o c t a l o n e  the t o t a l •  t h e removal o f t h e c a r b o n y l  ( 1 2 4 ) , was n o t n e c e s s a r y  since this  trans-  45 f o r m a t i o n had a l r e a d y been a c c o m p l i s h e d sequence  leading t o octalone  .  Therefore  (124) c o n s t i t u t e s  s y n t h e s i s o f (+) i s o l o n g i f o l e n e  t h e above  a formal  total  (114).  • S l i g h t d i f f e r e n c e s i n H N.M.R. c o u l d b e a c c o u n t e d f o r s i n c e t h e above measurements were t a k e n i n C D C 1 w h i l e t h e l i t e r a t u r e v a l u e s were t a k e n i n CC1.. T h e change i n s o l v e n t i s known to vary chemical s h i f t s s l i g h t l y . However, when o c t a l o n e (124) was r e m e a s u r e d i n C C l . t h e c h e m i c a l s h i f t s m a t c h e d . 3  6 9  -153-  III  AN APPROACH TO  ZIZAANE-TYPE SESQUITERPENOIDS  To g a i n access to the zizaane c l a s s of s e s q u i t e r p e n o i d s we  now  turned our a t t e n t i o n to the dienone  earlier  i t was  the n i t r i l e  (166).  As mentioned  our i n t e n t i o n to convert the dienone  (171)  v i a a hydrocyanation  reaction.  (166)  into  This trans-  f o r m a t i o n , i f s u c c e s s f u l , would p r o v i d e a q u i c k e n t r y i n t o the,  CN  Zizaane  (166)  Class  (171)  zizaane c l a s s of s e s q u i t e r p e n e s  since octalone  (17%)  has a l -  ready been converted i n t o a number of members o f t h i s f a m i l y of  compounds. Treatment of the dienone  (166) w i t h a 6 f o l d excess  of  68 d i e t h y l aluminum cyanide i n benzene  f o r 16 hours a t room temper-  ature a f f o r d e d a f t e r p r e p a r a t i v e t h i n l a y e r chromatography, the n i t r i l e octalone structure 2250 cm  (172).  (172). The  ^, which was  a b s o r p t i o n a t 1670  cm  The  s p e c t r a l data were i n accord w i t h  i n f r a r e d spectrum e x h i b i t e d a b s o r p t i o n a t a s s i g n e d t o the n i t r i l e moiety, and 1  due  to the  a 8-unsaturated ;  a c o n s i d e r a t i o n of the ^H N.M.R. spectrum i t was a s s i g n the s t e r e o c h e m i s t r y of the n i t r i l e group.  an  ketone.  From  p o s s i b l e to A  molecular  -154-  model study of compound  (172) i n d i c a t e d t h a t H  and H are  CN  (172) symmetrically disposed with respect to H g i v e r i s e t o an A X system. 2  N.M.R. spectrum  and t h e r e f o r e should  T h i s proved t o be the case.  showed a t r i p l e t  The  a t 6=3.32 ( H ; J=3.5 H z ) , x  a sharp s i n g l e t a t 6=5.86 (IH, v i n y l p r o t o n ) , a doublet a t 6-=2.68 (H ,H ,J=3.5 Hz) and two high f i e l d A  B  s i n g l e t s a t .6 =1.16  and 6=1.20 due t o the two t e r t i a r y methyl p r o t o n s . Having  the n i t r i l e  convert t h i s n i t r i l e  (172) i n hand, i t was now necessary t o  i n t o the corresponding methyl e s t e r .  f o r t u n a t e l y due t o the l a c k o f s t a r t i n g m a t e r i a l , (dienone the s y n t h e s i s o f o c t a l o n e  (136a) was not c a r r i e d o u t .  COOCH  Un(166)),  -155-  Thus, i n c o n c l u s i o n , the i n t r o d u c t i o n of a f u n c t i o n a l i t y i n t o the dienone t i v e , p r o v i d i n g the n i t r i l e as found i n the and  zizaane  (166)  (172)  proved to be stereoselec-  with the n a t u r a l  c l a s s of s e s q u i t e r p e n e s .  novel route to t r i c y c l o  been developed c u l m i n a t i n g  nitrile  (6,2,1,0  1,6  stereochemistry An  attractive  ) undecane systems  has  i n the t o t a l s y n t h e s i s o f  (±) i s o l o n g i f o l e n e and has p r o v i d e d f e a s i b l e e n t r y i n t o the zizaane  a s h o r t and  c l a s s of  hopefully a  sesquiterpenoids.  -156-  EXPERIMENTAL PREPARATION OF OCTALONE (14 6)  COOCH  COOCH  i  ~>  (146)  (97) To  a stirred  solution  of potassium  pared  f r o m 19.0 g o f p o t a s s i u m m e t a l  under  an a t m o s p h e r e o f N  octalone  (97), over  i n 600 m l o f t - b u t y l  was added d r o p w i s e  2  a period  o f 15 m i n u t e s .  t h e n c o o l e d u s i n g an i c e b a t h , f o r 5 m i n u t e s , mcle ) o f f r e s h l y  distilled  methyl  T h e s o l u t i o n was a t which  f o r 1.5 h o u r s  acid  and e x t r a c t e d w i t h e t h e r .  oil.  t i m e ( 140 g, 1.0  The r e and t h e n  The c o m b i n e d  e t h e r e x t r a c t s were washed w i t h ^ 0 , aqueous s o d i u m dried  alcohol),  T h e m i l k y r e s i d u e was d i l u t e d w i t h H2O, n e u t r a l i z e d  with hydrochloric  brine,  (pre-  a t 3 5 ° C , ( 3 4 . 0 g, 0.16mole) c  i o d i d e was a d d e d .  s u l t i n g m i x t u r e was a l l o w e d t o r e f l u x concentrated.  t-butoxide  (MgSO^) a n d e v a p o r a t e d t o y i e l d  Distillation  under  thiosulfate,  32 grams o f c r u d e  r e d u c e d p r e s s u r e a f f o r d e d (31 g,'80%)  dure octalone (146) as a c l e a r o i l ; b.p. 118-122°C (bath_tPJiropj-atur^) at -1 0.4 mm  ;  ±.r. ( f i l m )  (ester carbonyl);  X  1710 cm  p.m.r. 6-5.90  (sat. carbonyl),  (t,lH,vinyl,  (s , 3H -C-0-CH,) 6 1 5 ( S, 6H, t e r t i a r y f  -1 1730 cm  J=4.0 Hz)6 =3.75  methyls) .  PREPARATION  OF DIENE  (14 7)  COOCH  A stirred mole  s u s p e n s i o n o f sodium h y d r i d e  ) i n 250 ml o f d r y d i m e t h y l s u l f o x i d e was s l o w l y h e a t e d  u n d e r an a t m o s p h e r e o f n i t r o g e n a t 75°C and k e p t ature  until  was t h e n  froathing  dimethyl  ester  bromide  f o r 15 m i n u t e s ,  an. a d d i t i o n a l ml o f water.  petroleum-ether dried  hour  under reduced  1.2 8  i n 350 ml o f  The r e s u l t i n g a solution  mixture o f the  ) i n 200 m l o f d i m e t h y l left to  m i x t u r e was e x t r a c t e d  with  and t h e combined e x t r a c t s were washed w i t h t o g i v e a crude  pressure afforded  (t,lH,vinyl  oil.  1  (8.0 g, 83%) o f pure diene (147); b.p.  3  1 C  m e t h y l ) , 5*  methyl). H  0 0  0 : 0  ( ester  (d o f d , 2 H , v i n y l H, J=  (s , 3H,-C-OCH )y$ -1.13 (s , 3H, t e r t i a r y  Anal. Calcd. f o r C  -1  ( u n s a t u r a t e d C=C); p.m.r.  H, J=4.2 Hz)6-4.70  (s , 3H, t e r t i a r y  brine,  Distillation  a t o.35nm; i . r . (fi.lrrti X 1735 c m . • max  1640, 1655, 890 cm  6.0,1.0) 6-3.67  mixture  of methyl  The r e a c t i o n m i x t u r e was  The r e s u l t i n g  120—125°C '(bath tenperature) carbonyl),  temper-  and t h e n q u e n c h e d by t h e a d d i t i o n o f  (MgSO^) and e v a p o r a t e d  6=5.80  and a s o l u t i o n  a t which time  (146) (10 g, 0.042 mole  at this  The r e a c t i o n  (75 g, 0.21 m o l e ) ,  s u l f o x i d e was added d r o p w i s e . stir  (1.5 h ) .  s u l f o x i d e was a d d e d d r o p w i s e .  was s t i r r e d keto  had ceased  c o o l e d t o room t e m p e r a t u r e  triphenylphosphonium  600  (4.8 g, 0.2  C, 76.88; H, 9.46.  Found:  -158-  C,  76.97; H,  9.60.  PREPARATION OF ALCOHOL (14 8) and  To  (149)  a s t i r r e d s o l u t i o n of (2.6 g, 37.0 mmol) 2-methy-2jbutene  in 40 ml of dry THF at 0 C and under an atmosphere of nitrogen was added C  14.5 ml for  of  1 hour at 0°C  40 ml THF 2.0  a 0.62 molar diborane solution i n THF.  was  a s o l u t i o n of diene  added and  cooled  to 0° and  After  The  stirring  (9.0 mmole) i n  the r e a c t i o n mixture was  hours at room temperature.  again  (147)  .  l e f t to  stir  r e a c t i o n mixture was  once  12 ml of 3N sodium hydroxide was  care-  f u l l y added f o l l o w e d by the c a r e f u l a d d i t i o n of 12 ml of hydrogen peroxide.  The  r e s u l t i n g mixture was  hours at room temperature and r e s i d u e was  d i l u t e d w i t h water and  combined ether and  concentrated.  afforded  (l.9g, '84%)  solumns showed two  compounds.  mixture of a l c o h o l s . the t r a n s - a l c o h o l 79-80°C.  The  (MgSO^),  D i s t i l l a t i o n under reduced  of a mixture of the a l c o h o l s  A  H  (14 8)and  G.L.C. analysis on sevoVal  N.M.R. spectrum showed a  G.L.C. c o l l e c t i o n on 10% O.S.  (149)  1.5  The r e s u l t i n g  e x t r a c t s were washed w i t h b r i n e , d r i e d  (149) ; b.p. 130-140°C (bath temperature) at 0.35 mm;  m.p.  stirred for  extracted with ether.  evaporated to g i v e a crude o i l .  pressure  30%  p l u s the c r y s t a l l i n e l a c t o n e  38  afforded  (150) *,  S p e c t r a l p r o p e r t i e s of the t r a n s - a l c o h o l  (149)  -159-  COOCH  (150)  (149) are as f o l l o w s : ]  i . r . (film)  X  max  3450 cm  1  ( h y d r o x y l ) , 1725 cm  1  (ester c a r b o n y l ) ; p.m.r. 6 =5.72 ( t , l H , v i n y l H, J=4 Hz), 3.66 fe, 3H,-CO-CH_ ), 3. 50,  3. 75 (AB p a r t o f an ABX system, 2H,-CH -OH, J  3  12 Hz, J  fix  2  A B  =  =5 Hz, J = 8 H z ) . A X  Anal. Calcd. f o r C  1 5  H  2 4  0 :  C, 71.39; H, 9.59.  3  Found:  C, 71.20;  H, 9.76. S p e c t r a l properties of lactone X 1720 c m max  (150) •,  (lactone c a r b o n y l ) ; p.m.r. 6=1.22  - 1  i . r . (CHC1 ) 3  (s , 6H, t e r t i a r y  m e t h y l s ) , 4.10, 4.56 (AB p a r t o f an ABX p a t t e r n , 2H, -C-0-CH_ -, 2  J  AB  = 1 2  H Z  ' AX J  = 4  H Z  ' BX J  Anal. Calcd. f o r C  1  4  H  2  = 2  q  H Z )  0 J 2  C, 76.33; H, 9.15.  Found:  H, 9.33. PREPARATION OF THE ACETATES (153) and (154)  COOCH.  GOOCH.  OAc (153)  (154)  C, 75.90;  -160-  A mixture of 10 g o f the a l c o h o l s  (148) and (149)  20 ml of a c e t i c anhydride and 40 ml p y r i d i n e was heated over a steam bath f o r 2 minutes and l e f t standing f o r 18 hours. and  a t room temperature  The r e a c t i o n mixture was then d i l u t e d with water  extracted with ether.  The combined ether e x t r a c t s were  washed w i t h IN h y d r o c h l o r i c a c i d , water, sodium water, b r i n e , d r i e d  bicarbonate,  (MgSO^) and evaporated t o g i v e a crude o i l .  D i s t i l l a t i o n under reduced pressure afforded (4.0 g, 94%) of acetates (153) and (154); b.p. 125-130 (bath temperature) at 0.55 mm. on  G.L.C. c o l l e c t i o n  10% O.V. 17 a t 240° a f f o r d e d a n a l y t i c a l samples o f t r a n s —  acetate  (155)1 >  (film) i 1740, 1720 c m * max  i.r.  - 1  (ester  carbonyls);  p.m.r.6 =0.98 ( s,3H,tertiary methyl), 1.05 (s, 3 H , t e r t i a r y methyl), 2.00 ( s, 3H,0-C-CH ) , 3.62fe..3H, -C-OCH ) , 4.10, 3.86 (AB p a r t 3  3  of ABX pattern,2H -CH -OAc /  Anal.  Calcd.  H, 9.10.  2  r  f o r C,_H_ O. : LI ZD 4 r  J =10.0 Hz, J = 5 . 0 Hz, J =6.0 H z ) . AB  AX  fix  C, 69. 36; H, 8.90.  Found:  C, 69.10;  S p e c t r a l data f o r the c i s - a c e t a t e i s as f o l l o w s J i.r.  (film)  6=0.80  X  1740, 1720 c m  max  -1  (ester c a r b o n y l s ) ; p.m.r. J  ( s , 3 H , t e r t i a r y methyl) , 1.19 ( s , 3 H , t e r t i a r y methyl),  2.04 ( s, 3H,OC-CH ) , 3.64 ( s, 3H,COCH_ ) , 3.8, 4.3 (AB p a r t o f ABX 3  pattern,  2H,-CH_ -CAc) , J = 1 4 Hz, J = 4 . 7 Hz, J = 4 . 7 H z ) .  Anal. Calcd. H, 8.78.  3  2  forC  AB  H 1 7  26°4  AX  :  C, 69.36; H, 8.90.  BX  Found:  C, 69.31;  -161-  PREPARATION OF OCTALONE  (155) AND (156)  COOCH LC  O-  O  (156)  (155) To a s t i r r e d  s o l u t i o n o f (4.1g, 13.9 mmol) of a  mixture of a c e t a t e s (153) and (154) i n 250 ml of dioxane was added (7.4g, 41.7 mmol) of N-bromosuccinimide, (2.8g, 27.8 mmol) of calcium carbonate, and 22ml of water. The reaction mixture was allowed to s t i r a t room temperature w h i l e being exposed t o direct  visible  light  (lamp) f o r 20 hours.  The r e a c t i o n mix-  t u r e was then f i l t e r e d through c e l i t e and the f i l t r a t e with ether.  The combined  e t h e r e x t r a c t s were washed w i t h water,  sodium t h i o s u l f a t e , b r i n e , d r i e d a crude o i l .  extracted  (MgSO^) and evaporated to y i e l d  D i s t i l l a t i o n under reduced p r e s s u r e a f f o r d e d (4.1g, S  a mixture of octalones (155) ana (156);b.p. 165-170 (bath temperature) at _ 0.25 mm. .  An a n a l y t i c a l sample o f each epimer was c o l l e c t e d  on 10% O.V. 17 a t 240°C.  The t r a n s - a c e t a t e  (155) had the  f o l l o w i n g s p e c t r a l and p h y s i c a l data}  i . r . (film) A  1700  (conj. c a r b o n y l ) J p.m.r.  cm  - 1  (ester c a r b o n y l s ) , 1660 cm  *=1.12 ( , 3H, t e r t i a r y s  methyl) ^ 1.18 ( ,3H, t e r t i a r y S  (s,3H,0-C-CH ) ^ 3 . 7 0 (s, 3H,-C-OCH ) 3  3  ABX p a t t e r n , 2H,-CH -OAc,J =10 Hz, 2  AB  ( S , 1 H , v i n y l p r o t o n ) ; m.p. c  1 / 24  a  1720,  x  methyl)  -2.04  3. 98, 4.18 (AB p a r t o f an )  Hz, J  =5 H z ) 6 . 2 2 :  fiX  }  62-64°C.  A n a l . C a l c d . f o r C,-,H_,O : H, 8.00.  1  m  D  C, 66.21; H, 7.84.  Found: C, 65.96;  -162-  Cis-keto 1720  cm  1  (ester  p.m.r. 6=1.27 2.04  acetate  carbonyls),  ( s, 3H, t e r t i a r y  (156),  i .  1670 cm methyl)  s  0 . 90  2  X  1740,  carbonyl); ( , 3H, t e r t i a r y s  methyl) ,  4.30 , 3.91 (AB p a r t o f  3  an ABX p a t t e r n , 2H ,-CH -QAc , p o o r l y  . (film)  (conj.  1  (s,3H,OC-CH ) , 3.70 ( , 3H,COCH_ ) 3  r  r e s o l v e d ) -6 . 22 y  (s,lH,  v i n y l H). Anal. Calcd.  for i7 2 °5 c  H  4  :  C  ' 66.21;  H  r 7.84.  F o u n d : C, 66.49;  ' H, 7.80.  PREPARATION OF KETAL ACETATE (160)  OAc .60) To a s t i r r e d solution o f l i t h i u m bromide (18.Og, 0.21mole) i n 250 ml of HMPA under an atmosphere o f nitrogen a t 60 C was added (5.Og,17.4mmol) q  of a mixture of octalones (155) and (156) . The reaction mixture was then heated at 140-150°C while nitrogen was bubbling through the s o l u t i o n . The reaction f l a s k was then cooled t o room temperature and water added to dissolve the excess l i t h i u m bromide. The reaction mixture was extracted with petroleum ether (7x50ml) and the combined extracts were washed with water (5x100ml) , brine (2x100ml), d r i e d (MgSO^) and evaporated t o y i e l d a crude o i l . G.L.C. analysis indicated that the crude mixture contained three compounds. D i s t i l l a t i o n under reduced pressure afforded (3.4g, 79%) o f decarbomethoxylated material as a mixture of three compounds; b.p. 140-155°C (bath temperature) a t 0.35mm.  -163-  H  This ditions without  l a t t e r m i x t u r e , was  subjected to ketalization  further purification. 'A solution  con-  o f t h e above  m i x t u r e (6.8g, 27itmol) , diethylene g l y c o l (2.5g, 4Qmmol), and a catalytic was  amount o f p - t o l u e n e s u l f o n i c  refluxed  f o r 20 h o u r s  r e a c t i o n m i x t u r e was with yield  pressure  ketal  afforded  (bath temperature)  i n 150 m l o f b e n z e n e  u s i n g a Dean-Stark  apparatus.  t h e n c o o l e d t o room t e m p e r a t u r e ,  sodium b i c a r b o n a t e , water, crude  acid  acetate  dried  (160).  The  washed  (MgS0 ) and e v a p o r a t e d t o 4  Distillation  under  reduced  (7.0g, 87%) of pure k e t a l acetate (160); b.p. l S O - i e O ^  a t 0.3mm. Upon cooling,the k e t a l acetate (160) c r y s t a l l i z e d .  R e c r y s t a l l i z a t i o n from petroleum-ether./ ether afforded white c r y s t a l s of k e t a l acetate (160); m.p. 101-102°C; i . r .  (CHCI3)  \  1725 cm"  1  (ester carbonyl) ;  -164-  (160)  p.m.r. <$=4.0 lm, 2H,-CH -OAc), 2  3.92  (s , 4H,ethylene k e t a l H) ,  2.00 (s,3H,OC-CH ) '1.03 ( s , 3 H , t e r t i a r y methyl) ^ 0.87 3  (s,3H,  t e r t i a r y methyl) . Anal. Calcd. f o r C,_H„0.: X / zb 4 69.19; H, 8.83.  C, 69.36; H, 8.90.  Found:  C,  PREPARATION OF KETAL ALCOHOL (161)  (161) To a mixture of l i t h i u m aluminum hydride  (10 eq)  -165-  i n f r e s h l y d i s t i l l e d THF (250 ml) was added dropwise (5.0g,_ 16.7mmol) of k e t a l acetate  (16 0) i n 50 ml o f THF.  f o r 1.5 hours and cooled was  The s o l u t i o n was r e f l u x e d  t o room temperature.  The r e a c t i o n  quenched by the c a r e f u l ( p o r t i o n wise) a d d i t i o n o f sodium  s u l f a t e de cany dr ate ..'Addition was continued until the excess lithium aluminum h y d r i d e was destroyed.  The r e s u l t i n g mixture was f i l -  t e r e d through c e l i t e and thoroughly washed w i t h e t h e r . f i l t r a t e was d r i e d alcohol  The  (MgSO^) and evaporated t o give crude k e t a l  (161) .Distillation under reduced pressure afforded (4.0g, 94%)  of ketal alcohol (161); b.p. 150-155°C (bath temperature) at 0.15 mm; i.r.  (film)  y _ A  3325 cm"  (hydroxyl);  1  p.m.r. 6=3.94 ( »4H, S  Iua X  e t h y l e n e k e t a l H) , 3.70 (m,2H,-CH -OH) 1.03 ( s , 3 H , t e r t i a r y 2  }  methyl) 0.83 ( s, 3H, t e r t i a r y methyl) . Mol.  Wt. c a l c d . f o r  C  H 1 5  24°3  :  252.1725.  Found  (high  r e s o l u t i o n mass spectrometry) 252.1697. PREPARATION OF KETAL TOSYLATE (162)  (162)  To a solution of k e t a l alcohol (161) ( 4.0g, 15.8 mmol) i n 50 ml of p y r i d i n e  was a d d e d 1 . 5 e q o f f r e s h l y r e c r y s t a l l i z e d  enesulfonyl  chloride.  temperature  f o r 1 2 hours, poured  for  T h e r e a c t i o n was l e f t  t o stand  i n t o ice-water  1 5 m i n u t e s , a n d t a k e n up i n e t h e r .  p-tolua t room  (200 ml),  stirred  T h e combined e t h e r e x -  -166-  t r a c t s were washed with c o l d dried  (IN) h y d r o c h l o r i c a c i d , water,  (MgSO^) and evaporated a t room temperature  p r e s s u r e to y i e l d a p a l e y e l l o w o i l . in  under  reduced  The crude o i l was d i s s o l v e d  a minimum amount of petroleum e t h e r , c o o l e d to -78°C, and  the f l a s k etched to induce c r y s t a l l i z a t i o n .  Recrystallization  from petroleum ether/acetone a f f o r d e d 6.5 g ()99%) o f pure ketal tosylate  (162) as white needles,- m.p.  (CHC1,)  0  x  1 1 9  4H,aromatic CTs) , 3.9 6 0.9 8  cm"  1  100-101°C;  i.r.  ( d o u b l e t ) ; p.m.r. 6 =7. 38 , 7. 82 (d,d,  protons, J=8.5 H z ) ^ 3.80-4.20 (complex m,2H,-CH 2  (s,4H, e t h y l e n e k e t a l H), ~2.45 ( s, 3H , aromatic methyl),  ( s, 3 H , t e r t i a r y methy1) , 0.81 ( s, 3H, t e r t i a r y m e t h y l ) .  Anal. Calcd. f o r C Found:  C, 6 5.18;  2 2  H  3 Q  0 S: 5  C, 65.01; H, 7.44; S, 7.88.  H, 7.40; S, 7.97.  PREPARATION OF KETO TOSYLATE (163)  (163) To a solution of (6.4g, 15.7mmol) o f keto tosylate (163) i n 125 ml o f a c e t o n e and 30 m l o f w a t e r was added of  concentrated s u l f u r i c  to  stir  of  saturated  f o r 0.75 h o u r s  acid.  d r o p w i s e , 2 ml  The r e a c t i o n m i x t u r e was  left  a t 5 0 ° C then poured into a s t i r r i n g solution  aqueous sodium  was e x t r a c t e d w i t h e t h e r .  bicarbonate. The combined  The r e s u l t i n g  ether extracts  mixture were  -167-  washed w i t h water u n t i l n e u t r a l , d r i e d  (MgSO^) and evaporated  under reduced p r e s s u r e a t room temperature to g i v e a crude yellow o i l . solvent X  iTiax  High vaccuum e v a p o r a t i o n removed the l a s t t r a c e s o f  to y i e l d  1720 c m  -1  (5.6 g , 99% ) of keto t o s y l a t e  (sat. c a r b o n y l ) ;  (163) } i . r .  (film)  p.m.r. 6 =7.28, 7.70 (d,d,4H,  aromatic protons, J=8.0 Hz), 3.8 ( m, 2H,-CH -CTs  2.3 (s,3H,  2  aromatic methyl), 0.90 (s, 3H, t e r t i a r y methyl), 0.72 (s , 3H , t e r t i a r y methyl). PREPARATION OF OCTALONE (165)  (165) To  a s o l u t i o n o f potassium t-butoxide  (2.5 eq)  pared from .616 g o f potassium i n 50 ml o f t - b u t y l followed  (pre-  alcohol  by e v a p o r a t i o n of the t - b u t y l a l c o h o l ) , i n 50 ml o f  f r e s h l y d i s t i l l e d HMPA, was added dropwise, under an atmosphere of n i t r o g e n ,  (2.3g, 6.3mmol) of keto tosylate (163) i n 50ml of HMPA. After  a d d i t i o n was complete the r e a c t i o n was s t i r r e d an a d d i t i o n a l 10 minutes and quenched by the a d d i t i o n o f water and 3N H C l . The r e s u l t i n g mixture was e x t r a c t e d The  (5x50 ml) w i t h petroleum  combined e t h e r e x t r a c t s were washed  (7x50 H 0 ) , d r i e d 2  (MgSO^) and evaporated t o y i e l d y e l l o w i s h wet c r y s t a l s . path d i s t i l l a t i o n - d i s c a r d i n g  material  ether.  Short  t h a t d i s t i l l e d below 70°C  and above 120°C- afforded 655mg of a colourless o i l ; b.p. 95-110°C (bath  -16 8-  tenperature ) at 0.015 mm. boiling  Chromatography on s i l i c a g e l o f the low  m a t e r i a l and r e s i d u e a f f o r d e d an a d d i t i o n a l 157 mg of a  crude yellow o i l . Short path d i s t i l l a t i o n of the latter yielded an additional (78mg, 4%) of octalone (165). Upon cooling , the octalone (165) crystallized. Recrystallization from petroleum ether/ether afforded (733mg, 64%) of octalone (165); m.p. 63-64°C; i . r . (CHC1.,) X j  1670 cm" , 1640 cm" 1  1  (ct,B unsaturated  ITlclX  carbonyl); p.m.r. S= 5.72 (s, IH, vinyl), 6= 1.36 (s, 6H, 2 quaternary methyls); u.v. y 238 (e 13,000); max Mol. Wt. Calcd. for ]_3 ^3 C  H  0:  190.1361. Found (high resolution mass spectrometry)  190.1357. PREPARATION  OF DIENONE (16 6)  (166) To a s t i r r e d s o l u t i o n o f o c t a l o n e (165) 70 ml o f dioxane, 64  was added 3 ml o f a c e t i c a c i d and 1.5 eq o f  DDQ  (666 mg).  and  f i l t e r e d through a bed o f c e l i t e  evaporated  The s o l u t i o n was r e f l u x e d f o r 17 hours, (1").  cooled  The f i l t r a t e was  and the r e s i d u e was e x t r a c t e d w i t h e t h e r .  The com-  b i n e d e t h e r e x t r a c t s were washed w i t h H 0, sodium b i c a r b o n a t e , 2  E^O u n t i l n e u t r a l , passed through a 1" l a y e r o f a c t i v i t y I I I alumina, d r i e d (MgSO^) and evaporated  t o y i e l d crude dienone  High vacuum d i s t i l l a t i o n a f f o r d e d . ( 0.285g , 60%) f c r y s t a l l i n e 0  (166).  -169-  dienone (166). Recrystallization from petroleum ether afforded pure crystals of dienone (166); m.p. 72-73°C; i . r . (CHC1J A  1660 cm , 1630 cm , 1601'cm" -1  -1  1  (due to cross conjugated carbonyl); p.m.r. 6= 7.02 (d, IH, J" =10Hz, vinyl) 2 3  6=6.30 (d of d, IH, J =2Hz, J =10Hz, vinyl), 6=5.99 (d, IH, J 1  2  32  2  ^2Ez) , 6=1.11  (s, 3H, quaternary methyl), 6=1.06 (s, 3H, quaternary methyl); u.v. u  247  ( e= 14,700)  Anal. Calcd. for C^^O:  C, 82.94; H, 8.57. Found: C, 82.65; H, 8.50.  PREPARATION OF OCTALONE (167)  (167)  To a s t i r r e d s o l u t i o n o f cuprous  i o d i d e (Q.861g, 0.425  mmol) i n 15 ml o f e t h e r a t 0°C under an atmosphere o f n i t r o g e n was added 5.3 ml o f 1.7 M methyl  lithium.  T h i s mixture was  then s t i r r e d an a d d i t i o n a l 10 minutes a t 0°C. A s o l u t i o n o f dienone  (166) (0.425 g; 2.26 mmole) i n 15 ml o f e t h e r was then  added over a p e r i o d o f 10 minutes. for  A f t e r s t i r r i n g a t 0°C  1 hour, t h e r e a c t i o n was quenched by the slow a d d i t i o n o f  a s a t u r a t e d s o l u t i o n o f ammonium c h l o r i d e . s t i r r e d f o r 20 minutes,  The s o l u t i o n was  t r a n s f e r r e d to a separatory funnel,  d i l u t e d w i t h 100 ml o f water and thoroughly e x t r a c t e d w i t h e t h e r . The combined e t h e r e x t r a c t s were washed w i t h water, b r i n e , d r i e d (MgSO.), and evaporated t o y i e l d a crude y e l l o w o i l .  Distilla-  -170-  t i o n under reduced pressure a f f o r d e d (0.375g,0.45mole)of octalone (167).  A n a l y t i c a l sample c o l l e c t e d on 10% O.V. 17 c r y s t a l l i z e d ^  m.p. 63-64°C;  i . r . (CHCl ) A  p.m.r. 6=5.72  3  m a x  1650, 1640 c m  ( s , l H , v i n y l H), 1.12  ( s , 3 H , t e r t i a r y methyl)  }  Anal. Calcd. f o r C  l 4  H  2 Q  1.02 0:  -1  (conj. c a r b o n y l ) ;  ( s, 3H, t e r t i a r y methyl) , 1.08  (d,3H,secondary methyl) .  C, 82.30; H, 9.87.  Found:  C, 81.98;  H, 10.00. PREPARATION OF DIENONE (169)  To a s o l u t i o n of o c t a l o n e in  (167) (0.325g, 1.51 mmol)  50 ml of THF , c o n t a i n i n g 2 ml of a c e t i c a c i d a t 45°C under  an atmosphere of N , was added 0.576 g (1.1 eq) of p y r i d i n i u m 2  hydrobromide perbromide .  The s o l u t i o n was l e f t  to s t i r f o r  one hour, c o o l e d , n e u t r a l i z e d with sodium b i c a r b o n a t e , and e x t r a c t e d with e t h e r .  The combined e t h e r e x t r a c t s were washed  w i t h water, d r i e d (MgSO^) and evaporated t o y i e l d the crude bromoketone  ( 100%).  The crude bromoketone  (0.457 g, 1.61 mmole) was  d i s s o l v e d i n 50 ml o f DMF c o n t a i n i n g 0.490 g (3.5 eq) o f l i t h i u m bromide and 0.420 g (3.5 eq) o f l i t h i u m carbonate and r e f l u x e d for  3 hours .  The r e a c t i o n mixture was then c o o l e d ,  w i t h water and e x t r a c t e d with petroleum e t h e r .  diluted  The combined  o r g a n i c e x t r a c t s were washed w i t h water, b r i n e , d r i e d (MgSO.)  -171-  and evaporated  to y i e l d  t i o n under reduced  0.307 g of a crude mixture.  pressure  a f f o r d e d .240  Distilla-  g o f a yellow o i l ; b.p.  135-140°C (bath temperature) at 0.2mm. G.L.C. analysis indicated three major compounds.  Chromatography of t h i s mixture  w i t h g r a d i e n t e l u t i o n u s i n g a mixture 67 mg  of petroleum  of s t a r t i n g m a t e r i a l (octalone  dienone  (168)  pure dienone  on s i l i c a g e l a f f o r d e d  (167)), 70 mg  as a c r y s t a l l i n e compound, and (169) ; i . r .  (film) X  m  =  1660,  v  1.12  Hz),, 2.00  ( , 3H, t e r t i a r y methyl) / 1. 20 s  Mol.Wt. C a l c d . f o r C mass s p e c t r o s c o p y ) ,  1 4  H  l n  O:  o f bromo-  (lOOmg, 40%) of  1630  cm  c o n j . c a r b o n y l ) ; p.m.r. 6=6.00 ( d , l H , v i n y l H, J=2 (d of d,lH, v i n y l H, J=2  ether-ether  -1  (cross  Hz)  ,6.14  (d,3H,vinyl methyl, J=2  Hz),  (s,3H, t e r t i a r y methyl) .  202.1357.  Found  (high r e s o l u t i o n  202.1321.  PREPARATION OF OCTALONE  (124)  (124)  To a s o l u t i o n of cuprous i o d i d e (5 eq) e t h e r at 0 ° c under an atmosphere of N l i t h i u m and the s o l u t i o n was  left  A s o l u t i o n of c r o s s conjugated  2  was  added  to s t i r at 0°C  dienone  (164)  i n 5 ml (5 eq)  of  of methyl  f o r 10 minutes.  (30mg, O..144mmol) in 2ml  ether was then added dropwise and the reaction was l e f t to s t i r for 5 hours at room temperature. The reaction was then quenched by the dropwise addition of a saturated solution of ammonium chloride.  -17 2-  The solution was stirred for 20 minutes, transferred to a separatory funnel, diluted with water, and thoroughly extracted with ether. The combined ether extracts were washed with water, brine, dried (MgSO^) and evaporated to yield a crude o i l . Chromatography of the crude o i l on s i l i c a gel afforded with * gradient elution using a mixture of petroleum ether/ ether (7mg,40%) of crystalline octalone (124); m.p. 53-54°C; p.m.r. 6= 5.7 (s, IH, vinyl) 6=1.14 (s, 3H, tertiary methy), 6=1.09 (s, 3H, tertiary methy), 6=1.05 (s, 3H tertiary methyl), 6=1.00 (s, 3H, tertiary methyl). Low resolution mass spectroscopy showed parent peak mass as 218. Mol. Wt. Calcd. for ^ 5 2 2 l » Found (high resolution mass spectrometry) C  H  0:  2  8  l 6 7 0  218.1692. PREPARATION OF KETO CYANIDE  (172)  Following the procedure of Nagata et a l  , (method B) ,  dienone (166) was treated with a six fold excess of diethyl aluminum cyanide in benzene (2.1M) at room temperature for two hours under an atmosphere of nitrogen. The reaction mixture was then poured into a 2N NaOH-  solution and  extracted with dichloromethane and the crude product was purified by preparative T.L.C..  The sample had spectral properties i n accord with  structure (172); i . r . A  2250 cm , 1670 cm -1  -1  ( conj. carbonyl); p.m.r.  6= 5.86 (s, IH, vinyl proton), 6=3.32 (t, IH, -CH-CN, J=3.5 Hz ),  Yield based on recovered starting material (14mg) .  -173-  2.68  (d,2H,J=3.5 Hz), 6 = 1.16  ,3H,tertiary  methyl).  (<;, 3 H , t e r t i a r y methyl) , 6=1.20  f  -174-  REFERENCES  1.  S.K. Malhotra and H.J. Ringold, J . Am. Chem. Soc. 86, 1997(1964).  2.  H.O. House,Modern Synthetic Reactions, (2nd Ed.) , Benjamin, New York, N.Y. (1972).  3.  R.A.Lee and W.Reusch, Tetrahedron Lett. 969 (1973).  4.  R.A.Lee, D. McAndrews, K.M.Patel and W.Reusch, Tetrahedron Lett. 965 (1973).  5.  L.Nedelec, J.C. Gasc and R.Bucourt, Tetrahedron, 30, 3263 (1974).  6.  H.J.Ringold and S.K.Malhotra, Tetrahedron Lett. 669 (1962).  7.  P. DeMayo, Molecular Rearrangements, Vol 1, Wiley& Sons, New York  8.  M.W.Rathke and D.Sullivan, Tetrahedron Lett. 4249 (1972).  9.  H.J.Ringold and O.Rosenkranz, J.Org.Chem.22,602 (1957).  10.  H.J.Ringold and S.K.Malhotra, J.Am.Chem.Soc.84 3402 (1962).  11.  A.J.Birch, J.A,K.Quartey and H.Smith, J.Chem.Soc. 1968 (1952) .  12.  J.M.Conia and A.Sandre-LeCaaz, Tetrahedron Lett. 305 (1962).  13.  A.Wu and V.Snieckos, Tetrahedron Lett. 2057 (1975).  14.  G.Stork and J.Benaim, J.Am.Chem.Soc. 93, 5938 (1971).  15.  G.Stork and A.A.Ponaras, J.Org.Chem. 41, 2937 (1976).  16.  E.J.Corey, L.S.Melvin J r . and M.P.Haslanger, Tetrahedron Lett.3117 (1975)  17.  G.Stork and G.Bimbaum, Tetrahedron Lett. 313 (1961) .  18.  E.L.Eliel, Stereochemistry of Carbon Compounds, McGraw-Hill, New york, 1967, pp. 198-202. R.W.Kierstead, R.P.Linstead and B.C.L.Weedon, J.Chem.Soc. 3610, 3616 (1952).  19. 20.  E.Piers, W. de Waal, and R.W.Britton, J.Am.Chem.Soc. 93, 5113 (1971) .  -175-  21.  W.Nagata, T.Sugasawa, M.Narisada, T.Wakabayasmi and Y.Hayase, J.Am.Chem.Soc. 89, 1483 (1967).  22.  R.B.Kelly, J.Zamecnik, and B.A.Beckett, Can. J.Chem. 50, 3455 (1972).  23.  J.E.McMurry and S.J.Isser, J.Am.Chem.Soc. 94, 7132  24.  R.B.Bates, G.Buchi, T.Matsuurs and R.R.Shaffer, J.Am.Chem.Soc. 82, 2327 (1960).  25.  G.Buchi, W.Hofheinz and J.V.Paukstelis, J.Am.Chem.Soc. 91, 6473 (1969).  26.  Netherlands Patent Appl. 6603853 (UpJohn Co.) C.A. 66, 65747 (1967).  27. 28.  J.J.Bonet, H.Wehrli and K.Schaffner, Helv. Chim. Acta. 45, 2615 (1962). O.Halpern, P.Crabbe, A.D.Cross, I . D e l f i n , L.Cervantes and A.Bowers, Steriods 4, 1 (1964). C.Mercier, A.R.Addas and P.Deslonschamps, Can.J.Chem. 50, 1882 (1972).  29.  (1972).  30.  P.Grafen, H.S.Kabbe, O.Roos, G.D.Diana, Tsung-tee L i , and R.B.Turner, J.Am.Chem.Soc. 90, 6131 (1968).  31.  R . L . C a r g i l l and T.E.Jackson, J.Org.Chem. 38, 2125  32.  G.Stork, A.Brizzolara, H.Landesman, J.Szmuszkovice and R . T e r r e l l , J.Am.Chem.Soc. 85, 207 (1963).  33.  J.A.Marshall and W.I.Fanta, J.Org.Chem. 29, 2501  34.  E.Fernholz and H.E.Stavely, Abstracts, 102nd Meeting of Am.Chem.Soc. A t l a n t i c C i t y , N.J., 39M (1941).  35.  H.Normant, Angew.Chem.Ind.Ed.Engl. 6, 1046  36.  G.W.Gokel and H.D.Durst, Aid.Chem.Acta. 9, 1 (1976).  37.  D.H.R.Barton, D.A.J.Ives and B.R.Thomas,J.Chem.Soc. 2056 (1955).  38.  J.C.Collins, W.W.Hess and F.J.Frank, Tetrahedron Lett. 3363 (1968).  39.  P.C.Mukharji and A.N.Ganguly, Tetrahedron, 25, 5281  40.  C.F.Lane, J.Org.Chem. 39, 1437  41.  W.G.Dauben and F.B.Rogan, J.Am.Chem.Soc. 79, 5002 (1957).  42.  V.Ramdas and S.Dev, Tetrahedron, 8, 42 (1960).  43.  J.R.Frahlao, R.Ranganathan, U.RamdasNayak, T.S.Santhanakri and S.Dev, Tetrahedron L e t t . 417 (1964).  (1973).  (1964).  (1967).  (1969).  (1974).  -176-  44.  T.S.Santhanakrishan, U.R.Nayak and S.Dev, Tetrahedron, 26, 641 (1970).  45.  R.R.Sobti and S.Dev, Tetrahedron, 26, 649 (1970).  46.  D.F.MacSweeney and R.Ramage, Tetrahedron, 27, 1481 (1971).  47.  F.Kido, H.Uda, and A.Yoshikoshi, Chem. Comm. 1335 (1969).  48.  F.Kido, H.Uda and A.Yoshikoshi, Tetrahedron Lett. 2815 (1967).  49.  F.Kido, H.Uda and A.Yoshikoshi, J.Chem.Soc.Perkin trans. 1, 1755 (1972)  50.  R.Sakuma and A.Yoshikoshi, Chem. Comm. 41 (1968).  51.  A.Deljac, W.D.Mackay, Connie S.J.Pan,Karel J.Wiesner and K.Wiesner, Can.J.Chem. 50, 726 (1972).  52.  R.M.Coates and R.L.Sowerby, J.Am.Chem.Soc. 94, 5386 (1972).  53.  G.Buchi, A.Hauser and J.Limacher, J.Org.Chem. 42, 3323 (1977).  54.  A.Bowers, T.G.Halsall E.R.H.Jones and A.J.Lemin, J.Chem.Soc. 2548 (1953) .  55.  R.Ranganathan, U.R.Nayak, T.S.Santhanakrishnan and S.Dev, Tetrahedron, 26, 621 (1970).  56.  E.J.Corey, R.B.Mitra and H.Uda, J.Am.Chem.Soc. 86, 485 (1964).  57.  A.S.Drieding and A.J.Tomasewski, J.Am.Chem.Soc. 77, 411 (1955).  58.  R.B.Woodward, A.A.Patchett, D.H.R.Barton, D.A.J.Ives and R.B.Kelley, J.Chan.Soc. 1131 (1957).  59.  R.Greenwald, M.Chaykovski and E.J.Corey, J.Org.Chem. 28, 1128 (1963).  60.  H.C.Brown, Tetrahedron, 12, 117 (1961).  61.  W.G.Dauben, M.Lorber and D.S.Fullerton,' J.Org.Chem. 34, 3587 (1969).  62.  B.W.Finucane and J.B.Thomson, Chem.Comm. 1220 (1969).  63.  J.E.McMurry and G.B.Wong, Synthetic Comm. 389 (1972).  64.  D.Walker and J.D.Hiebert, Chem. Rev. 67, 153 (1967).  65.  G.H.Posner, "Organic Reactions", Vol. 19, Chap. 1 (1972).  66.  D.V.C.Awang and Saul Wolfe, Can.J.Chem. 47, 706 (1969).  67.  R.Joly, J.Warnant, G.Nomine and D.Bertin, Bull.Soc.Chem. 366 (1958) .  -177-  W.Nagata, M.Yoshioka and M.Murakami, J.Am.Chem.Soc. 94, 4654 (1972). L.M.Jackman and S.Sternhall, "Application of N.M.R. Spectroscopy i n Organic Chemistry", Pergamon Press 2nd Ed. pp. 246. J.A.Davis, J.Herynk, S.Carroll, J.Bunds and D.Johnson, J,Org.Chem. 30, 415 (1965).  

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